Anthracycline-induced phospholipase A<Subscript>2</Subscript> inhibition

The purpose of this essay is to overview our findings that membrane-associated calcium-independent phospholipase A₂ is markedly inhibited by low, clinically relevant concentrations of anthracyclines. Our studies suggest that due to the essential role of this enzyme in membrane homeostasis, its inhibition can be one of the early culprits leading to anthracycline-induced cardiac dysfunction. The clinical importance and potential pharmaceutical use of this new phenomenon await further studies.     

Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties

The electrical and synaptic properties of neurons are essential for determining the function of the nervous system. Thus, understanding the mechanisms that control the appropriate developmental acquisition and maintenance of these properties is a critical problem in neuroscience. A great deal of our understanding of these developmental mechanisms comes from studies of soluble growth factor signaling between cells in the peripheral nervous system. The sympathetic nervous system has provided a model for studying the role of these factors both in early development and in the establishment of mature properties. In particular, neurotrophins produced by the targets of sympathetic innervation regulate the synaptic and electrophysiological properties of postnatal sympathetic neurons. In this review we examine the role of neurotrophin signaling in the regulation of synaptic strength, neurotransmitter phenotype, voltage-gated currents and repetitive firing properties of sympathetic neurons. Together, these properties determine the level of sympathetic drive to target organs such as the heart. Changes in this sympathetic drive, which may be linked to dysfunctions in neurotrophin signaling, are associated with devastating diseases such as high blood pressure, arrhythmias and heart attack. Neurotrophins appear to play similar roles in modulating the synaptic and electrical properties of other peripheral and central neuronal systems, suggesting that information provided from studies in the sympathetic nervous system will be widely applicable for understanding the neurotrophic regulation of neuronal function in other systems.     

Breast-feeding, self-exam, and exercise practices before and after reduction mammoplasty

The current indications for reduction mammoplasty include the relief of painful physical symptoms of macromastia. Numerous studies have demonstrated not only improvement in physical symptoms following reduction mammoplasty, but postoperative psychological benefits as well, including increased ability to participate in physical activity as a result of pain relief and decreased breast mass. Reduction mammoplasty may have additional effects on the patient's ability to breast-feed and perform breast self-exam. The present study is a retrospective study of the effects of reduction mammoplasty on breast-feeding, breast self-exam, physical symptoms, and physical activity. One-hundred and forty-one patients who underwent reduction mammoplasty at our institution between the years 1996-2005 agreed to participate in the study. Each was asked a series of questions in order to assess changes in symptoms and behaviors including breast-feeding and breast self-exam practices before and after the surgery. Patients were also asked questions regarding their pain symptoms and physical activity profiles. Ninety-seven percent of the participants claimed to have back, neck, and/or shoulder pain that was either significantly improved or completely resolved. Moreover, 100% of patients report that physical activity such as exercise was easier following reduction mammoplasty. Ninety-three percent of participants reported that performing breast self-exam following surgery was either the same (68%) or easier (25%) as a result of having less breast tissue. Eighty-nine percent of participants had no children following surgery, therefore effects on breast-feeding practices following reduction mammoplasty were not statistically significant. However, we suggest that when patients are seen in consultation or in the perioperative period, there is an opportunity to teach patients about the benefits of breast-feeding, and to assure patients that a pedicle flap reduction will likely allow breastfeeding. This is also a chance for physicians to teach patients how to perform breast self-examination and explain the importance of early breast mass detection.     

Differences in utilization of drug-eluting stents by race and payer

Numerous disparities in access to health care by race and gender have been identified in the literature. This study examines differences in the use of drug-eluting stents (DES) versus bare-metal stents (BMS) by race, payer, and income level. Data from New York State's Percutaneous Coronary Intervention Reporting System from July 2003 to December 2004 were used to examine use of DES (20,165 patients) relative to BMS (4,547 patients) by race, payer, and annual income level, controlling for a variety of patient and hospital characteristics. African-Americans were found to be less likely to receive DES than other races between July 2003 and March 2004 (adjusted odds ratio [OR] 0.56, 95% confidence interval [CI] 0.50 to 0.65) and between April 2004 and December 2004 (adjusted OR 0.74, 95% CI 0.61 to 0.90). These disparities were reduced (respective adjusted ORs 0.67, 95% CI 0.58 to 0.77 and 0.81, 95% CI 0.66 to 0.91) when controlling for admitting hospital and hospital volume, but were still significant. Medicaid/self-pay patients, and patients living in zip codes with median annual incomes between $20,000 and $30,000 were also less likely to receive DES in the first time period (adjusted respective ORs 0.80, 95% CI 0.68 to 0.93) and 0.85, 95% CI 0.75 to 0.96). In conclusion, African-Americans and low income groups receive DES less frequently than their counterparts compared with BMS. This is related to the hospitals where they are admitted, but not entirely.     

Why board of nursing disciplinary actions do not always yield the expected results

One of the ways boards of nursing serve to protect the public health, safety, and welfare is by removing from practice those nurses who fail to meet recognized standards of care or otherwise pose a public threat. Self-reporting and discovery through criminal background checks and reports from the court system or other regulatory bodies represent only small numbers of those disciplined. Most complaints investigated by a board are reported by nursing administrators, either chief nursing officers or nurse managers. Frequently, the reporting nurses provide the board with information from their own investigation that identifies the problem and the cause and includes supporting evidence. Based on their own independent investigation, the reporting nurses often assume that the outcome of board action is a foregone conclusion. Without understanding all of the ramifications of disciplinary processes and the requirements to protect the rights of the nurse that are guaranteed under the US Constitution, the final outcome decision can be totally different than anticipated and thus disappointing to the reporting nurse administrator. They could perceive the decision as wrong, nonsupportive, and discounting the efforts made by the reporting nurse. This unhappiness with the outcome causes vulnerability in the major reporting source to a board, namely, the relationship between the board and the nurse administrator. An initial step in mitigating this vulnerability is a better understanding by nursing administrators of the legal procedures that guide disciplinary processes and boards providing timely feedback to reporting nurses on the disposition of cases.     

Risk-scoring Method for Prediction of 30-Day Postoperative Outcome after Infrainguinal Surgical Revascularization for Critical Lower-limb Ischemia: a Finnvasc Registry Study

Background The aim of the present study was to develop a risk-scoring method for prediction of immediate postoperative outcome after infrainguinal surgical revascularization for critical limb ischemia. Methods The Finnvasc registry included data on 3,925 infrainguinal surgical revascularization procedures. This database was randomly divided into a derivation and a validation data set of similar sizes. Results In the overall series, 30-day postoperative mortality and major amputation rates were 3.1% and 6.3%, respectively. The 30-day postoperative mortality and/or limb-loss rate was 9.2%. Diabetes, coronary artery disease, foot gangrene, and urgent operation were independent predictors of 30-day postoperative mortality and/or major lower-limb amputation. A risk score was developed by assigning 1 point each to the latter risk factors. In the derivation data set, the 30-day postoperative mortality/amputation rates in patients with scores of 0, 1, 2, 3, and 4 were 7.7%, 6.4%, 11.1%, 20.4%, and 27.3%, respectively, (P < 0.0001); mortality rates were 1.3%, 2.3%, 4.1%, 7.7%, and 12.1%, respectively, (P < 0.0001); and major amputation rates were 6.4%, 4.3%, 7.1%, 12.7%, and 18.2%, respectively, (P < 0.0001). In the validation data set, the 30-day postoperative mortality/amputation rates in patients with scores of 0, 1, 2, 3, and 4 were 4.8%, 7.5%, 10.1%, 15.9%, and 22.2%, respectively, (P < 0.0001); mortality rates were 0.7%, 2.3%, 4.2%, 5.5%, and 14.8%, respectively, (P < 0.0001); and major amputation rates were 4.6%, 5.3%, 6.4%, 11.0%, and 14.0%, respectively (P = 0.011). Conclusions This simple risk-scoring method can be useful to stratify the immediate postoperative outcome of patients undergoing infrainguinal surgical revascularization for critical lower-limb ischemia.     

Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation

We employed a novel mouse line that expresses low levels of human tissue factor (TF) in the absence of murine TF to analyze the role of TF in gestation. Low-TF female mice had a 14-18% incidence of fatal postpartum uterine hemorrhage, suggesting that TF plays an important role in uterine hemostasis. Low-TF female mice mated with low-TF male mice had a 42% incidence of fatal midgestational hemorrhage (n = 41), whereas no fatal midgestational hemorrhages were observed in low-TF female mice mated with wild-type male mice (n = 43). Placentas of low-TF embryos from both low-TF and normal (+/-) TF females were abnormal and contained numerous maternal blood pools in the labyrinth. Placentas of TF null embryos surviving beyond embryonic day 10.5 exhibited similar defects. The mouse maternal-embryonic placental barrier consists of four cellular layers (layers I, II, and III and endothelial cells), where layer I lines the maternal lacunae. Comparison of TF-deficient placentas with control placentas by immunohistochemical and ultrastructural analyses revealed thinning of layer I and a reduction in the number of cellular contacts of layer I trophoblasts spanning the maternal blood space between adjacent trabeculae. These structural changes in low-TF and TF null placentas result in enlarged maternal lacunae, as determined by morphometric analysis, and placental hemorrhage, which leads to midgestational death of low-TF female mice. This study demonstrated that TF is required for uterine hemostasis and revealed an unexpected role of TF in the maintenance of the placental labyrinth.     

Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers

The ability of a series of synthetic analogues of ω-conopeptides MVIIA (SNX-111) and TVIA (SNX-185) to prevent electrically-evoked norepinephrine release from rat tail artery and hippocampal slice preparations was determined in an effort to identify voltage-sensitive calcium channel (VSCC) blockers that selectively target N-type VSCCs in central nervous system tissue. Electrical field stimulation (3 Hz, 1 ms in duration, 80 V for 1 min) caused a high and consistent tritium outflow from rat tail artery and hippocampal slice preparations preloaded with [³H]-norepinephrine. All conopeptides, chosen for their selective affinities for high-affinity SNX-111 binding sites (i.e., N-type VSCCs) over high-affinity ω-conopeptides MVIIC (SNX-230) binding sites (i.e., P/Q-type VSCCs), produced a concentration-dependent inhibition of calcium dependent electrically-evoked tritium outflow from both tail arteries and hippocampal slices; IC₅₀s ranged from 1.2 nM to 1.2 μM. Blocking potencies (IC₅₀s) in the tail artery assay were significantly correlated with those measured in the hippocampal slice preparation (r = 0.91, P = 0.00000012). There was a significant correlation between IC₅₀s for blockade of hippocampal norepinephrine release and the inhibition of high-affinity [¹²⁵I]-SNX-111 binding in rat brain synaptosomes (r = 0.76, P = 0.00028). Blockade of hippocampal norepinephrine release was not significantly correlated with the inhibition of high-affinity SNX-230 binding (r = 0.46, P = 0.056). Maximum inhibition of tritium outflow in the tail artery assay was 22 ± 1.4% of control, approximating the value (20.9 ± 16.0% of control) obtained in the absence of extracellular Ca²⁺. In contrast, the maximum inhibition of tritium release from hippocampal slices was 36.8 ± 2.5% of control (P < 0.05, compared to that of the tail artery assay). These results suggest that (1) N-type VSCCs alone mediate low frequency electrical stimulation-evoked neurotransmitter release from peripheral sympathetic efferents (tail artery) while both N-type and non-N type(s) mediate neurotransmitter release from CNS neurons (hippocampus); and (2) analogues of ω-conopeptides MVIIA and TVIA do not differentiate between N-type VSCCs mediating norepinephrine release from central and peripheral neural tissues. Received: 12 June 1997 / Accepted: 17 October 1997