Substantial and sustained reduction in under-5 mortality, diarrhea, and pneumonia in Oshikhandass, Pakistan: evidence from two longitudinal cohort studies 15 years apart.

BACKGROUND: Oshikhandass is a rural village in northern Pakistan where a 1989-1991 verbal autopsy study showed that diarrhea and pneumonia were the top causes of under-5 mortality. Intensive surveillance, active community health education and child health interventions were delivered in 1989-1996; here we assess improvements in under-5 mortality, diarrhea, and pneumonia over this period and 15 years later. METHODS: Two prospective open-cohort studies in Oshikhandass from 1989 to 1996 (Study 1) and 2011-2014 (Study 2) enrolled all children under age 60 months. Study staff trained using WHO guidelines, conducted weekly household surveillance and promoted knowledge on causes and management of diarrhea and pneumonia. Information about household characteristics and socioeconomic status was collected. Hurdle models were constructed to examine putative risk factors for diarrhea and pneumonia. RESULTS: Against a backdrop of considerable change in the socioeconomic status of the community, under-5 mortality, which declined over the course of Study 1 (from 114.3 to 79.5 deaths/1000 live births (LB) between 1989 and 1996), exceeded Sustainable Development Goal 3 by Study 2 (19.8 deaths/ 1000 LB). Reductions in diarrhea prevalence (20.3 to 2.2 days/ Child Year [CY]), incidence (2.1 to 0.5 episodes/ CY), and number of bloody diarrhea episodes (18.6 to 5.2%) seen during Study 1, were sustained in Study 2. Pneumonia incidence was 0.5 episodes /CY in Study 1 and 0.2/CY in Study 2; only 5% of episodes were categorized as severe or very severe in both studies. While no individual factors predicted a statistically significant difference in diarrhea or pneumonia episodes, the combined effect of water, toilet and housing materials was associated with a significant decrease in diarrhea; higher household income was the most protective factor for pneumonia in Study 1. CONCLUSIONS: We report a 4-fold decrease in overall childhood mortality, and a 2-fold decrease in childhood morbidity from diarrhea and pneumonia in a remote rural village in Pakistan between 1989 and 2014. We conclude that significant, sustainable improvements in child health may be achieved through improved socioeconomic status and promoting interactions between locally engaged health workers and the community, but that continued efforts are needed to improve health worker training, supervision, and the rational use of medications. TRIAL REGISTRATION: Not Applicable.

British Military surgical key performance indicators: time for an update?

BACKGROUND: Key performance indicators (KPIs) are metrics that compare actual care against an ideal structure, process or outcome standard. KPIs designed to assess performance in deployed military surgical facilities have previously been published. This study aimed to review the overall performance of surgical trauma care for casualties treated at Role 3 Camp Bastion, Medical Treatment Facility, Afghanistan, in light of the existing Defence Medical Services (DMS) KPIs. The secondary aims were to assess the utility of the surgical KPIs and make recommendations for future surgical trauma care review. METHODS: Data on 22 surgical parameters were prospectively collected for 150 injured patients who had primary surgery at Camp Bastion between 1 May 2013 and 20 August 2013. Additional information for these patients was obtained using the Joint Theatre Trauma Register. The authors assessed data recording, applicability and compliance with the KPIs. RESULTS: Median data recording was 100% (IQR 98%-100%), median applicability was 56% (IQR 10%-99%) and median compliance was 78% (IQR 58%-93%). One KPI was not applicable to any patient in our population. Eleven KPIs achieved >80% compliance, five KPIs had 80%-60% compliance and five KPIs had <60% compliance. Recommendations are made for minor modifications to the current KPIs. CONCLUSION: 78% compliance with the DMS KPIs provides a snapshot of the performance of the surgical aspect of military trauma care in 2013. The KPIs highlight areas for improvement in service delivery. Individual KPI development should be driven by evidence and reflect advances in practice and knowledge. A method of stakeholder consultation, and sequential refinement following evidence review, may be the right process to develop the future set of DMS KPIs.

High-throughput microfluidic single-cell digital polymerase chain reaction.

Here we present an integrated microfluidic device for the high-throughput digital polymerase chain reaction (dPCR) analysis of single cells. This device allows for the parallel processing of single cells and executes all steps of analysis, including cell capture, washing, lysis, reverse transcription, and dPCR analysis. The cDNA from each single cell is distributed into a dedicated dPCR array consisting of 1020 chambers, each having a volume of 25 pL, using surface-tension-based sample partitioning. The high density of this dPCR format (118,900 chambers/cm(2)) allows the analysis of 200 single cells per run, for a total of 204,000 PCR reactions using a device footprint of 10 cm(2). Experiments using RNA dilutions show this device achieves shot-noise-limited performance in quantifying single molecules, with a dynamic range of 10(4). We performed over 1200 single-cell measurements, demonstrating the use of this platform in the absolute quantification of both high- and low-abundance mRNA transcripts, as well as micro-RNAs that are not easily measured using alternative hybridization methods. We further apply the specificity and sensitivity of single-cell dPCR to performing measurements of RNA editing events in single cells. High-throughput dPCR provides a new tool in the arsenal of single-cell analysis methods, with a unique combination of speed, precision, sensitivity, and specificity. We anticipate this approach will enable new studies where high-performance single-cell measurements are essential, including the analysis of transcriptional noise, allelic imbalance, and RNA processing.

Comprehensive microRNA expression profiling of the hematopoietic hierarchy.

The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.

Dynamic analysis of MAPK signaling using a high-throughput microfluidic single-cell imaging platform.

Cells have evolved biomolecular networks that process and respond to changing chemical environments. Understanding how complex protein interactions give rise to emergent network properties requires time-resolved analysis of cellular response under a large number of genetic perturbations and chemical environments. To date, the lack of technologies for scalable cell analysis under well-controlled and time-varying conditions has made such global studies either impossible or impractical. To address this need, we have developed a high-throughput microfluidic imaging platform for single-cell studies of network response under hundreds of combined genetic perturbations and time-varying stimulant sequences. Our platform combines programmable on-chip mixing and perfusion with high-throughput image acquisition and processing to perform 256 simultaneous time-lapse live-cell imaging experiments. Nonadherent cells are captured in an array of 2,048 microfluidic cell traps to allow for the imaging of eight different genotypes over 12 h and in response to 32 unique sequences of stimulation, generating a total of 49,000 images per run. Using 12 devices, we carried out >3,000 live-cell imaging experiments to investigate the mating pheromone response in Saccharomyces cerevisiae under combined genetic perturbations and changing environmental conditions. Comprehensive analysis of 11 deletion mutants reveals both distinct thresholds for morphological switching and new dynamic phenotypes that are not observed in static conditions. For example, kss1Delta, fus3Delta, msg5Delta, and ptp2Delta mutants exhibit distinctive stimulus-frequency-dependent signaling phenotypes, implicating their role in filtering and network memory. The combination of parallel microfluidic control with high-throughput imaging provides a powerful tool for systems-level studies of single-cell decision making.

Complete genome sequence of a virulent isolate of Streptococcus pneumoniae.

The 2,160,837-base pair genome sequence of an isolate of Streptococcus pneumoniae, a Gram-positive pathogen that causes pneumonia, bacteremia, meningitis, and otitis media, contains 2236 predicted coding regions; of these, 1440 (64%) were assigned a biological role. Approximately 5% of the genome is composed of insertion sequences that may contribute to genome rearrangements through uptake of foreign DNA. Extracellular enzyme systems for the metabolism of polysaccharides and hexosamines provide a substantial source of carbon and nitrogen for S. pneumoniae and also damage host tissues and facilitate colonization. A motif identified within the signal peptide of proteins is potentially involved in targeting these proteins to the cell surface of low-guanine/cytosine (GC) Gram-positive species. Several surface-exposed proteins that may serve as potential vaccine candidates were identified. Comparative genome hybridization with DNA arrays revealed strain differences in S. pneumoniae that could contribute to differences in virulence and antigenicity.

Short communication: Cultivation of Lentinus edodes mycelia using whey permeate as an alternative growth substrate.

The major objective of this research was to use whey permeate as an alternative growth medium for the cultivation of mycelia of the edible mushroom Lentinus edodes and to find an optimum condition for solid-state cultivation. Response surface analysis was applied to determine the combination of substrate concentration (40 to 60 g of lactose/L), temperature (20 to 30 degrees C), and pH (4 to 6) resulting in a maximal mycelial growth rate. The radial extension rates, estimated by measuring the diameters of growing colonies on the Petri dishes, were used as the growth rate of the mycelia at different conditions. The conditions predicted to maximize the mycelial growth of 6.41 +/- 0.47 mm/d were determined to be 40 g of lactose/L, temperature 23.6 degrees C, and pH 5.0. It was concluded that a partial cubic equation could accurately model the response surface of, and predict optimal growth conditions for, L. edodes mycelia using whey permeate because the model prediction agreed with the experimental growth rate, 6.39 +/- 0.22 mm/d. The results suggest that whey permeate could be utilized as a growth substrate for the cultivation of mycelia from the edible mushroom L. edodes, enhancing the use of this by-product by the cheese manufacturing industry.

The interaction between aspartic acid 237 and lysine 358 in the lactose carrier of Escherichia coli.

The lacY from Escherichia coli strains 020 and AE43 have been cloned on plasmids which were designated p020-K358T and pAE43-D237N. These lacY mutants contain amino acid substitutions changing Lys-358 to Thr or Asp-237 to Asn, respectively. The charge neutralizing effect of each mutation is associated with a functional defect in melibiose transport which we exploited in order to isolate second site revertants to the melibiose-positive phenotype. Eleven melibiose-positive revertants of p020-K358T were isolated. All contained a second-site mutation converting Asp-237 to a neutral amino acid (8 to Asn, 1 to Gly, and 2 to Tyr). Twelve melibiose-positive revertants of pAE43-D237N were isolated. Two were second-site revertants converting Lys-358 to a neutrally Gln residue, while the remainder directly reverted Asn-237 to the wild-type Asp-237. We conclude that the functional intimate relationship between Asp-237 and Lys-358 suggests that these residues may be closely juxtaposed in three-dimensional space, possibly forming a 'charge-neutralizing' salt bridge.

Lactose transport mutants of Escherichia coli resistant to inhibition by the phosphotransferase system.

The lactose carrier activity of Escherichia coli is inhibited by the binding of dephosphorylated glucose enzyme III. Saier et al. ((1978) J. Bacteriol. 133, 1358-1367) isolated lacY mutants that escaped this inhibition. This communication reports the cloning and sequencing of one of the Saier mutants and the isolation, cloning and sequencing of another similar mutant. Both mutations resulted in amino acid substitutions on the middle cytoplasmic loop of the carrier (alanine-198 to valine and serine-209 to isoleucine). It is concluded that this cytoplasmic loop may be one of the sites of binding of glucose enzyme III.

Lower diagnostic accuracy of thallium-201 SPECT myocardial perfusion imaging in women: an effect of smaller chamber size.

OBJECTIVES: We attempted to formally compare the diagnostic accuracy of thallium-201 single-photon emission computed tomographic (SPECT) myocardial perfusion imaging in men and women and the effect of chamber size on accuracy. BACKGROUND: The diagnostic accuracy of conventional exercise testing has been shown to be lower in women. Less is known about the relative accuracy of perfusion imaging. Because of smaller body size, women have a smaller heart size than men, a factor that may reduce accuracy. METHODS: We identified 323 patients undergoing thallium-201 SPECT myocardial perfusion imaging who either had < 5% probability of coronary artery disease (CAD) by Bayesian analysis or who underwent cardiac catheterization within 60 days of stress testing. Patients with documented history of infarction, coronary artery bypass grafting, pathologic Q waves on the electrocardiogram, left bundle branch block or nonischemic cardiomyopathy were not included. We performed strict quantitative analysis, and receiver operating characteristic (ROC) curves were generated and the area under the curve was calculated for men and women. A size index was generated from the number of short-axis slices and average radius of each slice, and the group was classified as having a large or a small chamber size. The ROC areas of men and women with a large and a small chamber size were then compared. RESULTS: Diagnostic accuracy was lower in women than in men (ROC are 0.82 vs. 0.93, p < 0.05) despite similar values for peak heart rate and rate-pressure product and similar severity of CAD. There was a greater difference in accuracy between patients with a large versus a small chamber size (ROC area 0.94 vs. 0.73, p < 0.01) despite similar levels of exercise and severity of CAD. When we compared men and women in groups stratified by chamber size, we could not detect a significant difference between ROC area values of men and women (large: 0.94 men, 0.93 women, p = 0.77, power to detect difference in area of 0.15 = 91%; small: 0.79 men, 0.72 women, p = 0.58, power to detect difference in area of 0.15 = 35%). CONCLUSIONS: The diagnostic accuracy of thallium SPECT myocardial perfusion imaging is lower in women than in men. Most of the difference appears to be due to smaller left ventricular chamber size in women, although a small residual gender effect in smaller heart sizes cannot be entirely excluded. It is proposed that the most likely cause for this difference is the relatively greater effect of imaging blurring on smaller hearts.

Comparison of pulmonary uptake with transient cavity dilation after exercise thallium-201 perfusion imaging.

OBJECTIVES: The purpose of the study was to evaluate the relationship between elevated lung/heart ratio (LHR) and transient ischemic dilation (TID) after stress thallium-201 myocardial perfusion imaging and to provide further insight into the mechanism of cavity dilation. BACKGROUND: Because both LHR and TID have been identified as adjunctive markers of severe coronary disease they should be found in the same patients. Although the mechanism of LHR has been defined, that of transient dilation has not. METHODS: We identified 4,618 consecutive patients undergoing maximal exercise perfusion imaging with thallium-201. Lung/heart ratio and a dilation index were derived and compared to each other and to relevant clinical parameters. RESULTS: There was a very weak relationship between the LHR and dilation index (r = 0.15, p < 0.001). Defining a dilation index > or =1.10 and LHR > or =50% as abnormal revealed that 322 of the patients (7%) had TID only, 351 (7.8%) had LHR only and 40 (0.9%) had both. When compared to patients without these findings both TID and LHR had higher thallium stress defect and redistribution scores. When comparing subjects who had elevated LHR uptake to those who had TID, it was found that those with LHR were more likely to have had prior myocardial infarction (MI) (29% vs. 9%), coronary artery bypass grafting (22% vs. 8%), lower ejection fraction (34+/-17% vs. 55+/-11%) and had more evidence of ischemia based on thallium stress defect and redistribution scores. However, patients with cavity dilation had a higher frequency of positive electrocardiographic response (31% vs. 19%) despite lower scintigraphic markers. CONCLUSIONS: Although pulmonary uptake and transient cavity dilation have both been associated with severe coronary disease, they have a very weak correlation, which, in combination with the different clinical parameters associated with each, suggests that they represent different pathophysiologic responses to exercise-induced ischemia. Our data support the hypothesis that TID represents transient subendocardial ischemia rather than physical dilation from increased end-diastolic pressure.

Iodine-123 phenylpentadecanoic acid and single photon emission computed tomography in identifying left ventricular regional metabolic abnormalities in patients with coronary heart disease: comparison with thallium-201 myocardial tomography.

Iodine-123 phenylpentadecanoic acid (IPPA) is a synthetic long chain fatty acid with myocardial kinetics similar to palmitate. Two hypotheses were tested in this study. The first hypothesis was that IPPA imaging with single photon emission computed tomography (SPECT) is useful in the identification of patients with coronary artery disease. Fourteen normal volunteers (aged 27 +/- 2 years) and 33 patients (aged 54 +/- 11 years) with stable symptomatic coronary artery disease and at least one major coronary artery with luminal diameter narrowing greater than or equal to 70% were studied with symptom-limited maximal exercise testing. The IPPA (6 to 8 mCi) was injected 1 min before the termination of exercise, and tomographic imaging was performed beginning at 9 min and repeated at 40 min after the injection of IPPA. Nine of the normal volunteers and 13 of the patients had a second examination performed at rest on another day. Using the limits of normal as 2 SD from the normal mean values, 27 of the 33 patients with coronary artery disease demonstrated abnormalities in either the initial distribution or the clearance of IPPA, or both. Nineteen of the 33 patients had a maximal variation of activity distribution of greater than or equal to 25% on the 9 min IPPA images. Twenty-two of the 33 patients had a maximal variation in IPPA washout greater than 17% and 17 had a washout rate less than or equal to 2%. There was good agreement between the location of significant coronary artery stenoses and abnormalities in the initial distribution and clearance of IPPA. The second hypothesis tested was that IPPA imaging is as or more sensitive and, therefore, complementary to thallium-201 imaging in the identification of exercise-induced ischemia in patients. Twenty-five of the 33 patients underwent both thallium-201 and IPPA tomographic imaging after symptom-limited maximal exercise testing. The amount of exercise performed by each patient during both studies was similar. Twenty-one of the 25 patients had abnormal IPPA tomographic studies, whereas 18 had abnormal thallium-201 tomographic studies (p = NS). The results of this study suggest the following conclusions: 1) iodine-123 phenylpentadecanoic acid imaging using single photon emission computed tomography and exercise provides a sensitive and relatively noninvasive method for identifying abnormalities in myocardial metabolism associated with significant coronary artery stenoses, and 2) iodine-123 phenylpentadecanoic acid is at least as sensitive as thallium-201 for this purpose using tomographic imaging and exercise testing.

Preliminary report of an ongoing phase I/II dose range, safety and efficacy study of iodine-123-phenylpentadecanoic acid for the identification of viable myocardium.

An agent that can accurately and cost-effectively identify viable myocardium is needed to select the patients most likely to benefit from myocardial revascularization. Iodine-123-phenylpentadecanoic acid (IPPA) is a synthetic radiolabeled fatty acid that has shown promise in evaluating patients with coronary artery disease (CAD). IPPA has unique metabolic properties that may make it superior to other single-photon agents used for this task. A Phase I/II study is underway to evaluate safety, dose range and efficacy of IPPA in assessing viability and predicting functional recovery after revascularization. Patients between the ages of 21 and 75 with angiographically documented CAD, who were being referred for coronary revascularization, were recruited. The patients were randomized to receive 2, 4 or 6 mCi of IPPA and then underwent sequential SPECT imaging at 4, 12, 20, 28 and 36 min after injection. Radionuclide ventriculography and perfusion imaging were performed before and again 8 wk after revascularization. Myocardial metabolic activity of IPPA was analyzed and compared to the preinjection and postejection fractions. There were no significant adverse effects from the administration of IPPA. Image quality was dose-dependent; the 2-mCi dose was not consistently acceptable for quantitative analysis. These preliminary data show that IPPA is safe and can produce myocardial images of good quality when 4 mCi or more are used. Early results are encouraging but more experience will be needed to define the role of IPPA in identifying myocardial viability.

Attenuation correction of thallium SPECT using differential attenuation of thallium photons.

The greatest limitation of 201Tl for the diagnosis of coronary artery disease remains the high soft-tissue attenuation of its low energy photons. However, thallium also emits a smaller number of higher energy photons. Since photons of higher energy undergo less attenuation, it was postulated that the amount of attenuation could be ascertained from the ratio of the low-to-high energy photon counts. A planar phantom was used to derive a regression equation relating attenuation to the count ratio of the low and high energy peaks. A three-dimensional heart phantom was constructed and SPECT images were obtained in air and water. Application of the attenuation correction algorithm to the SPECT images of the phantom in water produced images quantitatively similar to that obtained in air. We conclude that by using differential photon attenuation, correction of 201Tl SPECT using a single order post-processing technique is feasible. This technique may allow for more accurate analysis of thallium myocardial perfusion scintigraphy.

Prediction of improvement in left ventricular function with iodine-123-IPPA after coronary revascularization.

UNLABELLED: Iodine-123-phenylpentadecanoic acid (IPPA) is a synthetic fatty acid suitable for myocardial imaging. This study is the result of a Phase I/II trial to evaluate IPPA's ability to predict functional recovery in patients undergoing coronary revascularization. METHODS: Twenty-three patients with documented coronary disease underwent sequential SPECT imaging with IPPA before and radionuclide ventriculography both before and 8 wk after revascularization. Software was developed to evaluate myocardial IPPA metabolism and to determine the fraction of the left ventricle with intermediate metabolism. RESULTS: There was a significant correlation between initial IPPA uptake and final LVEF. The fractional area of the left ventricle demonstrating IPPA metabolism in the intermediate metabolic range was significantly higher in patients who demonstrated a 5% or greater increase in EF after revascularization (0.90 +/- 0.08 versus 0.78 +/- 0.17, p = 0.04). When only the patients who received complete revascularization were evaluated, there was a more significant difference (improved 0.92 +/- 0.05 versus 0.74 +/- 0.17, p = 0.011). Taking a lower limit of 1 s.d. from the mean, (87%) the six patients who had > or = 5% increase in LVEF after revascularization had more than 87% of the left ventricle in the intermediate metabolic range, whereas seven of ten patients whose change in LVEF was < 5% had less than 87% in the intermediate metabolic range (p = 0.011). CONCLUSION: In this initial experience, the amount of myocardium in the intermediate metabolic range is associated with improvement in LVEF after revascularization, especially in patients receiving complete revascularization.

Effect of patient obesity on the accuracy of thallium-201 myocardial perfusion imaging.

The effects of patient habitus (e.g., breast attenuation in women and diaphragmatic attenuation in men) have long been recognized as factors that reduce the accuracy of myocardial perfusion imaging. Although it has long been assumed that patient obesity effects accuracy, this has never been formally evaluated. We studied the effects of patient obesity, defined as a body mass index (BMI) > or = 30, on 607 patients who underwent exercise thallium-201 single-photon emission computed tomography (SPECT). Because the effects of obesity are most likely mediated through increased photon attenuation and scatter, we also evaluated the effects of other markers of patient size: body surface area (BSA) and patient weight. Accuracy was determined by performing quantitative analysis and measuring the area under the receiver operating characteristic curve (AUC). Obesity was associated with significantly lower accuracy (AUC 0.86 +/- 0.03 vs 0.92 +/- 0.02, p <0.05) despite similar estimates of maximal coronary blood flow (as estimated by heart rate and rate-pressure product at peak exercise) and severity of coronary disease. There were no significant differences attributable to either patient weight or BSA. Weight and BSA correlated significantly with left ventricular chamber size whereas BMI did not. We conclude that the accuracy of quantitative SPECT thallium-201 is significantly reduced by patient obesity and that although BSA and weight are also associated with increased attenuation, they have no effect on accuracy, which is most likely due to the compensating effects of increased chamber size.

Abnormal myocardial fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging.

The radioidinated synthetic fatty acid iodine-123 phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 +/- 11 vs 18 +/- 4, p less than 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 +/- 8 vs 17 +/- 6 for the apical short-axis section, p less than 0.05; 26 +/- 7 vs 18 +/- 5 for the basal short-axis section, p less than 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p less than 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.

Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21(WAF1/CIP1) predicts survival and good response to platinin-based chemotherapy.

Immunohistochemistry for p53, p21(WAF1/CIP1), and Ki-67 provides insight into the molecular events controlling the cell cycle. We tested the hypothesis that these cell cycle markers will aid in the clinical evaluation of ovarian and primary peritoneal surface epithelial neoplasms (SENs). Paraffin sections from a retrospective surgical series of 117 SENs were immunostained with anti-p53 (clone DO7, Novacastra Laboratories, UK), anti-p21(WAF1/CIP1) (clone EA10, Oncogene Science, Cambridge, MA), and anti-Ki-67 (clone MIB-1, Immunotech, Westbrook, ME). The Ki-67 proliferation index (Ki-67PI) and immunoreactivity were evaluated. One hundred seventeen SENs reacted as follows: p53 50%+ and p21(WAF1/CIP1) 65%+. Ki-67PI ranged from 4% to 88% (mean/median = 44/46%). p53 reactivity associated with transitional cell histology, decreased p21(WAF1/CIP1) staining, increased Ki-67PI, architectural/nuclear grade, and stage (P < .05, 1 x 10(-7), .01, .05/.0001, .001,). p21(WAF1/CIP1) staining was associated with endometrioid/clear cell histology, decreased Ki-67PI, architectural/nuclear grade, and stage (P < 05/.05, .05, .01/1 x 10(-8), 1 x 10(-5)). Ki-67PI associated with increased architectural/nuclear grade but not mucinous histology (P < 1 x 10(-5)/1 x 10(-6), .01). Sixty-seven patients had disease at last follow-up; 53 were dead of disease at 0 to 67 months (mean/median, 21/18), and 14 were alive with disease at 12 to 224 months (mean/median, 56/40). Fifty patients were disease free at 5 to 214 months (mean/median, 59/41). Predictors of survival include decreased Ki-67PI, stage, architectural/nuclear grade (P < 1 x 10(-6), 1 x 10(-10), 1 x 10(-10)/.005) and p21(WAF1/CIP1) IMS (multivariate P < 1 x 10(-6)). p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases necessary for cell cycle progression, functions as a key checkpoint in cell cycle control. Immunoreactivity for p21(WAF1/CIP1) provides prognostic information independent of other histological and clinical predictors, p53 IMS, and Ki-67PI in this series of 117 PTs with SENs. Our preliminary data suggest an interrelationship between p21(WAF1/CIP1) expression and an effective clinical response to platinin-based chemotherapy, both associated with apoptosis. Further investigation seems warranted.

Postpartum multivessel coronary dissection.

A 29-year-old woman had an acute myocardial infarction 5 days after giving birth. Serial coronary angiography showed multiple progressive coronary artery dissections, which eventually involved both the right and left coronary trees. Persistent cardiogenic shock necessitated emergent orthotopic heart transplantation. Examination of the cardiectomy specimen confirmed the presence of multiple myocardial infarctions, coronary artery dissection, and fibromuscular dysplasia of the coronary arteries. Fibromuscular dysplasia combined with changes in the arterial ground substance and hormonal milieu attributable to pregnancy or parturition are proposed as possible causes of coronary artery dissection in this case.

Severe transmural myocardial ischemia after dipyridamole administration implicating coronary steal.

Myocardial perfusion imaging with coronary vasodilators is routinely used for patients with suspected coronary disease who are unable to exercise. Since these agents work by increasing blood flow without significantly changing myocardial oxygen demand, they generally do not produce ischemia. A minority of patients show evidence of ischemia which some investigators suggest is due to a coronary steal phenomenon, but this has been challenged by several investigators. We present the case of a patient who developed severe transmural myocardial ischemia manifested by ST-segment elevation and severe perfusion defects which occurred after dipyridamole administration and which were reversed with aminophylline and nitroglycerin. This case supports the notion that coronary vasodilation with dipyridamole can induce a coronary steal.