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Biomedical subjects

M Silver

Publications and source records attributed to M Silver.

At least 19 recordsLinked to original sources

Fetal cardiac calcifications: report of four prenatally diagnosed cases and review of the literature.

Fetal cardiac calcifications are defined as diffuse hyperechogenicities in the different layers of the heart. This is an uncommon fetal ultrasound finding associated with significant myocardial dysfunction. We report four cases with massive fetal myocardial calcifications detected on prenatal ultrasound at 18-22 weeks' gestation and associated, in all cases, with significant cardiac dysfunction. Detailed fetal echocardiographic evaluation, chromosome analysis, and an extensive search for intrauterine infection as a cause of these abnormalities, were carried out on all cases. A thorough autopsy was performed on all deceased fetuses and postnatal investigation of the sole survivor was performed. Two of our patients chose to interrupt their pregnancies, one fetus suffered intrauterine demise, and one child was born alive. In all of our cases the karyotypes were normal, and no specific infectious etiology or maternal autoantibody was noted. Histopathology findings in the non-survivors included myo- and epicardial calcification maximal at the base of the heart. The living child has findings suggestive of an intrauterine infection, although no infectious entity was identified. Long-term follow-up showed sensorineural hearing loss and severe developmental delay.

Calcinosis↗

Real-time perfusion imaging with low mechanical index pulse inversion Doppler imaging.

OBJECTIVES: We sought to determine how successful pulse inversion Doppler (PID) imaging would be in detecting myocardial perfusion defects during dobutamine stress echocardiography. BACKGROUND: By transmitting multiple pulses of alternating polarity (PID) at a low mechanical index, myocardial contrast enhancement from intravenously injected microbubbles can be detected using real-time frame rates. Pulse inversion Doppler imaging was performed in 117 patients during dobutamine stress echocardiography by using an intravenous bolus of a perfluorocarbon-filled, albumin-(Optison: n = 98) or liposome- (Definity: n = 19) encapsulated microbubble and a mechanical index of <0.3. The visual identification of myocardial contrast defects and wall motion abnormalities was determined by blinded review. Forty of the patients had quantitative angiography (QA) performed to correlate territorial contrast defects with stenosis diameter >50%. RESULTS: There was a virtual absence of signal from the myocardium before contrast injections in all patients. Bright myocardial opacification at peak stress was observed in at least one coronary artery territory at frame rates up to 25 Hz in 114 of the 117 patients during dobutamine stress echocardiography. Regional myocardial contrast defects at peak stress were observed in all 30 patients with >50% stenosis in at least one vessel (13 with single-vessel and 17 with multivessel disease). Contrast defects were observed in 17 territories subtended by >50% diameter stenosis that had normal wall motion at peak stress. Overall agreement between QA and myocardial contrast enhancement on a territorial basis was 83%, as compared with 72% for wall motion. CONCLUSIONS: Pulse inversion Doppler imaging allows the detection of myocardial perfusion abnormalities in real-time during stress echocardiography and will further add to the quality and sensitivity of this test.

Albumins↗

Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia.

BACKGROUND: We investigated the therapeutic potential of ex vivo expanded endothelial progenitor cells (EPCs) for myocardial neovascularization. METHODS AND RESULTS: Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium and harvested 7 days later. Myocardial ischemia was induced by ligating the left anterior descending coronary artery in male Hsd:RH-rnu (athymic nude) rats. A total of 10(6) EPCs labeled with 1,1'-dioctadecyl-1 to 3,3,3',3'-tetramethylindocarbocyanine perchlorate were injected intravenously 3 hours after the induction of myocardial ischemia. Seven days later, fluorescence-conjugated Bandeiraea simplicifolia lectin I was administered intravenously, and the rats were immediately killed. Fluorescence microscopy revealed that transplanted EPCs accumulated in the ischemic area and incorporated into foci of myocardial neovascularization. To determine the impact on left ventricular function, 5 rats (EPC group) were injected intravenously with 10(6) EPCs 3 hours after ischemia; 5 other rats (control group) received culture media. Echocardiography, performed just before and 28 days after ischemia, disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC group than in the control group by day 28. Regional wall motion was better preserved in the EPC group. After euthanization on day 28, necropsy examination disclosed that capillary density was significantly greater in the EPC group than in the control group. Moreover, the extent of left ventricular scarring was significantly less in rats receiving EPCs than in controls. Immunohistochemistry revealed capillaries that were positive for human-specific endothelial cells. CONCLUSIONS: Ex vivo expanded EPCs incorporate into foci of myocardial neovascularization and have a favorable impact on the preservation of left ventricular function.

Animals↗

The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors.

Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, characterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.

Angiopoietin-1↗

Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis.

Formation of new blood vessels in the adult animal (i.e., angiogenesis) is an important event for tissue repair and for tumor growth and metastasis. Angiogenesis involves the migration and proliferation of endothelial cells. We have investigated the role of the growth suppressor p27(Kip1) (p27) on endothelial cell function in vitro and angiogenesis in vivo. We have generated Ad-TetON, a replication-deficient adenovirus that constitutively expresses the reverse tet-responsive transcriptional activator, and Ad-TRE-p27, which drives expression of p27 under the control of the tet response element. Western blot analysis demonstrated doxycycline-dependent overexpression of p27 in human umbilical vein endothelial cells (HUVECs) coinfected with Ad-TetON and Ad-TRE-p27, which resulted in a marked inhibition of DNA replication and cell migration in vitro. Inducible overexpression of p27 in cultured HUVECs inhibited the formation of tubelike structures and, when applied in a murine model of hind limb ischemia, reduced hind limb blood flow recovery and capillary density. These findings thus underscore a novel role of p27 in regulating endothelial cell migration in vitro and angiogenesis in vivo, suggesting a novel anti-angiogenic therapy based on inducible p27 overexpression.

Adenoviridae↗

Reversal of experimental diabetic neuropathy by VEGF gene transfer.

The pathogenetic basis for diabetic neuropathy has been enigmatic. Using two different animal models of diabetes, we have investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. Nerve blood flow, as measured by laser Doppler imaging or direct detection of a locally administered fluorescent lectin analogue, was markedly attenuated in rats with streptozotocin-induced diabetes, consistent with a profound reduction in the number of vessels observed. A severe peripheral neuropathy developed in parallel, characterized by significant slowing of motor and sensory nerve conduction velocities, compared with nondiabetic control animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of treated animals were similar to those of nondiabetic control rats; constitutive overexpression of both transgenes resulted in restoration of large and small fiber peripheral nerve function. Similar experiments performed in a rabbit model of alloxan-induced diabetes produced comparable results. These findings support the notion that diabetic neuropathy results from microvascular ischemia involving the vasa nervorum and suggest the feasibility of a novel treatment strategy for patients in whom peripheral neuropathy constitutes a secondary complication of diabetes.

Animals↗

Evaluation of a new computer intervention to teach people with autism or Asperger syndrome to recognize and predict emotions in others.

This randomized controlled trial looked at the effect of a new computer program designed to teach people with autistic spectrum disorders to better recognize and predict emotional responses in others. Two groups of 11 children (age 12-18) with autism or Asperger syndrome at two special schools participated: one group used the computer program for 10 half-hour sessions over 2 weeks. Within-program data showed a significant reduction in errors made from first to last use. Students were assessed pre- and post-intervention using facial expression photographs, cartoons depicting emotion-laden situations, and non-literal stories. Scores were not related to age or verbal ability. The experimental group made gains relative to the control group on all three measures. Gains correlated significantly with the number of times the computer program was used and results suggest positive effects. Further research could assess whether these gains generalized into real life or improved performance on theory of mind measures.

Adolescent↗

The Challenging Behaviour Scale (CBS): development of a scale for staff caring for older people in residential and nursing homes.

OBJECTIVES: A review of behavioural rating scales identified the need for a measure of resident behaviours that staff in care homes for older people find difficult to manage. A 25-item, broad-based rating scale, the Challenging Behaviour Scale (CBS), was developed to meet this need and its psychometric properties were examined. DESIGN: Cross-sectional surveys. METHODS: Ratings of 484 residents, living in 16 homes across England, were used to examine four methods of collecting inter-rater reliability data. Ratings of 382 residents living in 13 homes were used to evaluate criterion validity and to establish norms. Six further homes were used to explore qualitatively the validity of the suggested norms. Ratings of 98 residents living in four further homes were used to examine concurrent validity. The predictive validity of the CBS 'challenge' score was evaluated, using time-sampled direct observation of challenging behaviour in 237 residents, living in 11 homes. RESULTS: The scale records staff reports of the incidence, frequency and 'management difficulty' of resident behaviour and it can also identify 'challenging residents' through a computed score. It has good internal consistency, good test-retest reliability and adequate validity. Inter-rater reliability is good when staff receive training or when staff groups of at least three, of mixed qualifications, complete the scale. Norms are suggested for prospective studies of the prevalence of challenging behaviour. CONCLUSIONS: The CBS is quick to complete and may have potential for the evaluation of psychosocial interventions in care settings. It is, as far as we know, the first staff observational rating scale that is based on the reports of care staff, who constitute the backbone of residential care provision. Suggestions for improvements in criterion and content validity are outlined.

Aged↗

Interactively visualizing data warehouses.

As healthcare costs continue to rise, along with the urgency to control these costs, timely analyses of operational data stored in data warehouses have become critical. Although healthcare organizations have begun to amass large volumes of raw data within data warehouses, many have yet to capitalize on that valuable information. Many clinical and financial events are recorded each day, yet few of these data are leveraged to increase organizational awareness and performance. Because the development and implementation of a data warehouse requires significant time and capital, as well as highly skilled labor, the need to more fully leverage this considerable investment demands techniques that facilitate detailed data exploration, analysis, and the subsequent communication of findings. This article describes how the effective display of complex relationships in data can be used to discover areas of variance in large, changing data warehouses.

Critical Pathways↗

Case study: how to apply data mining techniques in a healthcare data warehouse.

Healthcare provider organizations are faced with a rising number of financial pressures. Both administrators and physicians need help analyzing large numbers of clinical and financial data when making decisions. To assist them, Rush-Presbyterian-St. Luke's Medical Center and Hitachi America, Ltd. (HAL), Inc., have partnered to build an enterprise data warehouse and perform a series of case study analyses. This article focuses on one analysis, which was performed by a team of physicians and computer science researchers, using a commercially available on-line analytical processing (OLAP) tool in conjunction with proprietary data mining techniques developed by HAL researchers. The initial objective of the analysis was to discover how to use data mining techniques to make business decisions that can influence cost, revenue, and operational efficiency while maintaining a high level of care. Another objective was to understand how to apply these techniques appropriately and to find a repeatable method for analyzing data and finding business insights. The process used to identify opportunities and effect changes is described.

Chicago↗

Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.

Animal studies and preliminary results in humans suggest that lower extremity and myocardial ischemia can be attenuated by treatment with angiogenic cytokines. The resident population of endothelial cells that is competent to respond to an available level of angiogenic growth factors, however, may potentially limit the extent to which cytokine supplementation enhances tissue neovascularization. Accordingly, we transplanted human endothelial progenitor cells (hEPCs) to athymic nude mice with hindlimb ischemia. Blood flow recovery and capillary density in the ischemic hindlimb were markedly improved, and the rate of limb loss was significantly reduced. Ex vivo expanded hEPCs may thus have utility as a "supply-side" strategy for therapeutic neovascularization.

Animals↗

Mortality of sea lions along the central California coast linked to a toxic diatom bloom.

Over 400 California sea lions (Zalophus californianus) died and many others displayed signs of neurological dysfunction along the central California coast during May and June 1998. A bloom of Pseudo-nitzschia australis (diatom) was observed in the Monterey Bay region during the same period. This bloom was associated with production of domoic acid (DA), a neurotoxin that was also detected in planktivorous fish, including the northern anchovy (Engraulis mordax), and in sea lion body fluids. These and other concurrent observations demonstrate the trophic transfer of DA resulting in marine mammal mortality. In contrast to fish, blue mussels (Mytilus edulus) collected during the DA outbreak contained no DA or only trace amounts. Such findings reveal that monitoring of mussel toxicity alone does not necessarily provide adequate warning of DA entering the food web at levels sufficient to harm marine wildlife and perhaps humans.

Animals↗

Rationale and design of the OPTIME CHF trial: outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure.

BACKGROUND: The optimal management of an acute exacerbation of chronic heart failure (CHF) is uncertain. There is little randomized evidence available to support the various treatment strategies for patients hospitalized with an exacerbation of CHF. Inotropic agents may produce beneficial hemodynamic effects, and although they are currently used in these patients, their effect on clinical response and impact on clinical outcome is unclear. We present a unique and simple study designed to determine whether a treatment strategy for CHF exacerbations that includes an intravenous agent with inotropic properties can reduce hospital length of stay and lead to improved patient outcome. METHODS: The OPTIME CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial is an ongoing multicenter, randomized, placebo-controlled trial of a treatment strategy for patients with acute exacerbations of CHF. The design of this study provides a novel approach to the evaluation of treatment strategies in the care of this population. The OPTIME CHF design uses early initiation of intravenous milrinone as both an adjunct to the best the medical therapy and to facilitate optimal dosing of standard oral therapy for heart failure. Patients with known systolic heart failure requiring hospital admission for a CHF exacerbation are randomly assigned within 48 hours of admission to receive a 48-hour infusion of either intravenous milrinone or placebo. The primary end point of this design is a reduction in the total hospital days for cardiovascular events within 60 days after therapy. Enrollment of 1000 patients began July 7, 1997, at 80 US centers and is projected to conclude in late 1999.

Adolescent↗

Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy.

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

Animals↗

Conduction issues.

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Atrial Fibrillation↗

Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.

Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing beta-galactosidase under the transcriptional regulation of an endothelial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1- or Tie-2-expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.

Animals↗