Organophosphate insecticide poisoning with monocrotophos-induced fabricated illness in a 7-year-old girl with refractory seizures over a 4-year period.

Munchausen syndrome by proxy is a form of abuse in which an adult, usually the mother, deceives health workers by exaggerating, falsifying or directly inducing psychological or physical symptoms in the child victim for psychological gratification. In 2013, the American Academy of Pediatrics coined the term 'caregiver-fabricated illness in a child' to describe this form of child abuse. A 7-year-old girl had many encounters with health workers over a period of 4 years and presented with evolving clinical features including refractory seizures and red urine for which she was followed up as a case of acute intermittent porphyria. She was later discovered to be the victim of chronic monocrotophos organophosphate poisoning by her mother. If all medical staff who manage children are to avoid becoming inadvertent participants in medical child abuse, this case report is an important reminder that a high index of suspicion is warranted in cases which present a diagnostic dilemma and who respond unexpectedly to treatment.Abbreviations AIP: Acute intermittent porphyria; APSAC: American Professional Society on the Abuse of Children; ASM: anti-seizure medication; CFIC: caregiver-fabricated illness in a child; CT: computed tomography: DVT: deep vein thrombosis; EEG: electroencephalogram: ESR: erythrocyte sedimentation rate; HDW: high-dependency ward; ICU: intensive care unit; LFT: liver function test; MBP: Munchausen syndrome by proxy; NICU: neonatal intensive care unit; RFT: renal function test; TB: Tuberculosis; UTH-CH: University Teaching Hospitals Children's Hospital.

Using reconfigurable microfluidics to study the role of HGF in autocrine and paracrine signaling of hepatocytes.

Cancer, developmental biology and tissue injury present multiple examples where groups of cells residing in close proximity communicate via paracrine factors. It is nearly impossible to dissect such cellular interactions in vivo and is quite challenging in vitro. The goal of this study is to utilize a reconfigurable microfluidic device in order to study paracrine signal exchange between groups of primary hepatocytes in vitro. Previously, we demonstrated that hepatocytes residing on protein spots containing collagen and hepatocyte growth factor (HGF) spots expressed epithelial (hepatic) phenotypes and also rescued them in neighboring hepatocytes on collagen spots that did not receive direct HGF stimulus. Herein, we designed a microfluidic device with parallel fluidic channels separated by retractable (reconfigurable) walls and employed this device to investigate interactions between groups of HGF-stimulated and unstimulated hepatocytes. Using a novel reconfigurable microfluidic device, we demonstrate that cultivation of HGF-containing protein spots upregulates the production of endogenous HGF in hepatocytes and that these HGF molecules diffuse over, causing phenotype enhancement in the recipient cells. We also show that selective treatment of the recipient hepatocytes with a c-met inhibitor (SU11274) diminishes the rescue effect, as gauged by the down-regulation of albumin and HGF expression. Our study is one of the first to demonstrate paracrine signaling via HGF in primary hepatocytes. More broadly, tools and methods described here may be used to study paracrine signaling in other types of cells and will have relevance for various fields of biomedical research from cancer to immunology.

Long-term survival benefits of thrombolysis: the Royal College of General Practitioners' myocardial infarction study.

OBJECTIVE: To investigate whether there is a long-term survival benefit from receipt of thrombolysis in routine care particularly pre-hospital thrombolysis, using 20 year mortality data from the RCGP myocardial infarction (MI) cohort study. METHODS: During 1991-92 the RCGP MI study assessed GP delivery of thrombolysis. Participants who received pre-hospital thrombolysis (n = 290), thrombolysis in hospital (n = 781) or no thrombolysis (n = 2021) were followed and mortality data collected to June 2012. The relationship between thrombolysis and survival time was analysed using Cox regression at 28 days, 1, 5, 10, 15 years post-AMI, and at end of follow-up (~20 years post-AMI). RESULTS: Compared to those who did not receive it, participants who received thrombolysis had a significant survival benefit at 28 days [adjusted hazard ratio (HR) 0.72, 95% confidence interval (CI): 0.58-0.90]; 1 year (adjusted HR 0.69, 95% CI: 0.57-0.83); 5 years (adjusted HR 0.76, 95% CI: 0.66-0.86); 10 years (adjusted HR 0.85, 95% CI: 0.77-0.95) and 15 years (adjusted HR 0.88, 95% CI: 0.80-0.96) post-AMI until end of follow-up (adjusted HR 0.92, 95% CI: 0.84-1.00). Pre versus in-hospital thrombolysis did not appear beneficial, although there was evidence among the pre-hospital group that short symptom onset-to-needle times conferred greater benefit. CONCLUSIONS: We found substantial long-term survival benefits associated with thrombolysis when used in routine care. Although primary percutaneous coronary intervention (pPCI) is now the choice treatment, thrombolysis remains an important option when pPCI cannot be delivered within 120 minutes of diagnosis.

Finite element modeling and experimental characterization of crosstalk in 1-D CMUT arrays.

Crosstalk is the coupling of energy between the elements of an ultrasonic transducer array. This coupling degrades the performance of transducers in applications such as medical imaging and therapeutics. In this paper, we present an experimental demonstration of guided interface waves in capacitive micromachined ultrasonic transducers (CMUTs). We compare the experimental results to finite element calculations using a commercial package (LS-DYNA) for a 1-D CMUT array operating in the conventional and collapsed modes. An element in the middle of the array was excited with a unipolar voltage pulse, and the displacements were measured using a laser interferometer along the center line of the array elements immersed in soybean oil. We repeated the measurements for an identical CMUT array covered with a 4.5-microm polydimethylsiloxane (PDMS) layer. The main crosstalk mechanism is the dispersive guided modes propagating in the fluid-solid interface. Although the transmitter element had a center frequency of 5.8 MHz with a 130% fractional bandwidth in the conventional operation, the dispersive guided mode was observed with the maximum amplitude at a frequency of 2.1 MHz, and had a cut-off frequency of 4 MHz. In the collapsed operation, the dispersive guided mode was observed with the maximum amplitude at a frequency of 4.0 MHz, and had a cut-off frequency of 10 MHz. Crosstalk level was lower in the collapsed operation (-39 dB) than in the conventional operation (-24.4 dB). The coverage of the PDMS did not significantly affect the crosstalk level, but reduced the phase velocity for both operation modes. Lamb wave modes, A0 and S0, were also observed with crosstalk levels of -40 dB and -65 dB, respectively. We observed excellent agreement between the finite element and the experimental results.

Plasminogen activators: a comparison.

Thrombolytic drugs play a crucial role in the management of patients with acute myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis, acute thrombosis of retinal vessel, extensive coronary emboli, and peripheral vascular thromboembolism. Recognition of the importance of fibrinolytic system in thrombus resolution has resulted in the development of different fibrinolytic agents. Now a days several newer plasminogen activators with different pharmacokinetic and pharmacodynamic properties have been developed to treat thrombotic disease, which are fibrin specific with prolonged half-life and can be administered as a single bolus.

Clinical and economic outcomes in thrombolytic treatment of peripheral arterial occlusive disease and deep venous thrombosis.

PURPOSE: Over the past 2 decades the use of thrombolytic therapy in the management of peripheral occlusive diseases, most notably peripheral arterial occlusion (PAO) and deep venous thrombosis (DVT), has become an accepted and potentially preferable alternative to surgery. We examined the period when urokinase was in short supply and subsequently unavailable, to explore potential differences in clinical outcome and economic effect between urokinase and recombinant tissue plasminogen activator (rt-PA). MATERIAL AND METHODS: Data were obtained from the Premier Perspective Database, a broad clinical database that contains information on inpatient medical practices and resource use. The study population included all patients hospitalized in 1999 and 2000 with a primary or secondary diagnosis of PAO or DVT. Incidence was calculated for common adverse events, including bleeding complications, intracranial hemorrhage, amputation, and death. Cost data were also abstracted from the database, and are expressed as mean +/- SD. RESULTS: Demographic variables were similar in the urokinase and rt-PA groups. The rate of bleeding complications was similar in the urokinase and rt-PA groups. There were no intracranial hemorrhages in the urokinase group, compared with a rate of 1.5% in the rt-PA PAO group (P = .087) and 1.9% in the rt-PA DVT group (P = .175). The in-hospital mortality rate was lower in the urokinase-treated PAO subgroup (3.6% vs 8.5%; P = .026), but a similar finding in the DVT subgroup did not achieve statistical significance (4% vs 9.8%; P = .069). While pharmacy costs were greater in the urokinase-treated group (US 5472 dollars +/- US 5579 dollars vs US 3644 dollars +/- US 6009 dollars, P < .001; PAO subgroup, US 11,070 dollars +/- US 15,409 dollars vs US 6150 dollars +/- US 12,398 dollars, P = .003), overall hospital costs did not differ significantly between the 2 groups. This finding appears to be explained by a shorter hospital stay and reduced room and board costs in the urokinase-treated group. CONCLUSION: There were significant differences in outcome in patients with PAO and DVT who received treatment with urokinase and rt-PA. While pharmacy costs were significantly greater when urokinase was used, reduction in length of stay accounted for similar total hospital costs compared with rt-PA. These findings must be considered in the context of the retrospective nature of the analysis and the potential to use dosing regimens that differ from those in this study.

The costs and benefits of community thrombolysis for acute myocardial infarction : a decision-analytic model.

BACKGROUND: There is evidence that the earlier a patient reaches hospital and receives thrombolysis, the better the outcome. The GREAT (Grampian Region Early Anistreplase Trial) directly addressed the issue of early thrombolysis by evaluating, in a randomised controlled trial, the efficacy of thrombolysis in the community compared with that administered in hospital. OBJECTIVE: This paper aimed to model the cost and benefits of community compared with hospital thrombolysis from the UK NHS perspective, using efficacy data from the GREAT. METHODS: A decision-analytic approach was used to model these two alternatives. Resource use and cost estimates were estimated for a single tertiary centre. Estimates of effectiveness in life-years were obtained from the 4-year follow-up for patients recruited to the GREAT, using declining exponential approximation of life expectancy. Costs are in pounds sterling, 2000/1 values. RESULTS: Community thrombolysis had an average life expectancy of 12.48 years and hospital thrombolysis had an average life expectancy of 12.39 years. Costs were 361 pounds sterling for community thrombolysis and 300 pounds sterling for hospital thrombolysis. Community thrombolysis led to an additional 0.09 years of life-expectancy gained compared with hospital thrombolysis at an additional cost of 61 pounds sterling per patient. Therefore, the incremental cost per life-year gained for the community thrombolysis service over the hospital thrombolysis service was 667 pounds sterling. Sensitivity analysis showed that estimates of cost per life-year gained were most sensitive to the estimates of survival. CONCLUSION: This model suggests that, from the UK NHS perspective, implementing community thrombolysis may lead to extra survival but at extra cost over hospital thrombolysis. Although the incremental cost per life-year is modest, judgements still have to be made, however, as to whether the extra benefits estimated are worth the additional resources required. This requires consideration of the local context in which the service may be introduced.

Current perspectives on reperfusion therapy for acute ST-segment elevation myocardial infarction: integrating pharmacologic and mechanical reperfusion strategies.

The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.

Prehospital thrombolysis with reteplase: the Nijmegen/Rotterdam study.

OBJECTIVE: The objective of this observational study was to assess time from electrocardiogram diagnosis to treatment and time from pain onset to treatment with double bolus reteplase compared to current therapy with streptokinase or bolus anistreplase in 2 cities (Rotterdam and Nijmegen) in the Netherlands, where prehospital thrombolysis is an established way of treatment of acute myocardial infarction. METHODS: Prehospital thrombolysis is performed using electrocardiogram diagnosis by the ambulance service as well as bolus anistreplase for treatment in Nijmegen, and streptokinase infusion in Rotterdam. Reteplase or anistreplase/streptokinase was assigned open label to patients according to order of presentation on a 1-to-1 basis. All patients were treated with nitrates sublingually and aspirin orally. Time intervals were recorded by the ambulance staff. RESULTS: In total, 250 patients were treated between April 1, 1999 and August 1, 2000. Reteplase was used in 120 patients and anistreplase/streptokinase in 130 patients. Using double bolus reteplase resulted in a significantly shorter time to treatment: a median of 81 minutes compared to a median of 104 minutes with the established therapy (P <.0001). There were no differences in mortality, aborted myocardial infarction, hemorrhagic stroke or the need for rescue angioplasty between the groups. CONCLUSION: In prehospital thrombolysis, double bolus reteplase is associated with a shorter time to treatment than bolus anistreplase or infusion of streptokinase.

Factors associated with delay in reperfusion therapy in elderly patients with acute myocardial infarction: analysis of the cooperative cardiovascular project.

BACKGROUND: Many elderly patients with an acute myocardial infarction (AMI) do not receive thrombolysis within 30 minutes of hospital arrival as recommended by the American College of Cardiology/American Heart Association Guidelines. We sought to identify factors associated with delay in administration of thrombolysis after arrival to the hospital in these patients and to determine whether this delay is associated with increased mortality rates. METHODS AND RESULTS: By using the Cooperative Cardiovascular Project database, we identified patients who received thrombolysis for an AMI. The patients were stratified into groups by time to thrombolysis after hospital arrival. Among a cohort of 17,379 patients, 22.2% received thrombolysis in the first 30 minutes after hospital arrival. Patients treated after the first 30 minutes were more likely to be older, be female, be diabetic, have a history of hypertension or heart failure, and have less marked ST elevation. They were also more likely to be admitted to smaller hospitals with a lower volume of AMIs and to hospitals without a cardiac catheterization laboratory. The 30-day mortality rate was significantly lower for patients treated within the first 30 minutes. After adjustments were made for clinical and hospital characteristics, delays in therapy beyond 30 and 90 minutes were associated with an increase in 1-year mortality rates of 9% and 27%, respectively, compared with delays for patients treated within 30 minutes. CONCLUSIONS: After hospital arrival, time to treatment with thrombolytic therapy is longer than recommended in a significant proportion of patients. Clinical characteristics and institutional factors are associated with the delay in treatment. The more rapid treatment of appropriate elderly patients with an AMI probably will reduce mortality rates.

Supervision of thrombolysis of acute myocardial infarction using telemedicine.

The treatment of acute myocardial infarction (MI) constitutes a significant problem in remote geographical areas of Greece. Furthermore, thrombolysis, the treatment of choice in the early phase of acute MI, requires the supervision of an expert. We have used thrombolytic treatment, using telemedicine, in remote medical centres. The Onassis Cardiac Surgery Centre was linked to six remote Aegean islands via telemedicine systems which permitted the transmission of 12-lead electrocardiograms (ECGs). The thrombolytic agent anistreplase was administered to patients with acute MI. Supervision, including consultation for treatment of complications, was achieved using the telemedicine system. One hundred and fifty-two ECGs were transmitted during 24 months, of which 108 (71%) indicated specific treatment of a cardiac condition. Ten cases were diagnosed as having acute MI and eight of these were treated with anistreplase. All patients survived acute MI and complications were treated locally. The application of thrombolytic treatment in acute MI is feasible in remote areas, with the use of a telemedicine system.

Cleavage of surfactant-incorporating fibrin by different fibrinolytic agents. Kinetics of lysis and rescue of surface activity.

Incorporation of surfactant into polymerizing fibrin causes loss of surface activity and marked retardation of clot lysis by plasmin (Günther and colleagues, Am. J. Physiol. 1994;267:L618-L624). We compared the efficacy of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), activated anisoylated streptokinase-plasminogen activator complex (APSAC), and plasmin to dissolve surfactant-incorporating fibrin. Alveofact was employed as a natural surfactant source, and plasminogen was coincorporated into the fibrin matrix at a physiologic ratio to fibrin. Fibrinolysis was quantified by the release of tracer from (125)I-labeled fibrin, and the pattern of split products was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. In addition, we investigated the fibrinolysis-related restoration of surface activity by measurement in the pulsating bubble surfactometer. Concentrations of all fibrinolytic agents were chosen to effect approximately 40% lysis of clot material in the absence of surfactant (control). When incorporated into the fibrin matrix, but not when admixed after clot formation, surfactant inhibited the cleavage of fibrin by all fibrinolytic agents in a dose-dependent manner. Interestingly, t-PA and u-PA were significantly less inhibited than was plasmin or APSAC. The pattern of arising fibrin scission products was identical for all fibrinolytic approaches and was independent of surfactant incorporation. Adsorption and minimum surface tension-lowering properties of Alveofact were almost completely lost upon incorporation into fibrin, but surface activity was fully restored upon sustained clot lysis with all fibrinolytic agents. We conclude that the fibrinolytic capacity of all agents investigated is markedly inhibited by surfactant incorporation in fibrin, but this inhibition is significantly less pronounced in the agents employing preincorporated plasminogen (t-PA and u-PA), as compared with plasmin and APSAC. The plasminogen activators may thus proffer to "rescue" pulmonary surfactant function by induction of fibrinolysis in the alveolar compartment.

A matched comparison of the combination of prehospital thrombolysis and standby rescue angioplasty with primary angioplasty.

This study sought to assess the rate of acute Thrombolysis In Myocardial Infarction (TIMI) trial grade 3 patency that can be achieved with the combination of prehospital thrombolysis and standby rescue angioplasty in acute myocardial infarction. No large angiographic study has been performed after prehospital thrombolysis to determine the 90-minute TIMI 3 patency rate in the infarct-related artery. Hospital outcome and artery patency were compared to 170 matched patients treated with primary angioplasty. Prehospital thrombolysis was applied 151+/-61 minutes after the onset of pain in 170 patients (56+/-12 years, 86% men), using recombinant tissue-type plasminogen activator, streptokinase, or eminase. Emergency 90-minute angiography was performed in every case. All patients in whom thrombolysis failed underwent rescue angioplasty. After thrombolysis alone, TIMI grade 3 flow in the infarct-related artery was observed in 108 patients (64%), TIMI grade 2 in 12 (7%), and TIMI grade 0 or 1 in 50 (29%). Rescue angioplasty was successful in 47 of 50 attempts. Overall, TIMI 3 patency was achieved in 91%, and additionally TIMI 2 flow in 7% of patients, an average of 113+/-39 minutes after thrombolysis and 55+19 minutes after admission. Therefore, < 2 hours after thrombolysis, only 2% of patients had persistent occlusion (TIMI 0 or 1) of the infarct-related artery. In-hospital mortality was 4% overall (7 of 170), and 3% in the 155 patients in whom TIMI 3 was obtained during the acute phase. Severe hemorrhagic complications occurred in 14 patients (8%) with 2 fatal cerebral hemorrhages (7% of patients required transfusions). The matched comparison with primary PTCA showed no significant difference in hospital outcome. Combined prehospital thrombolysis, 90-minute angiography, and rescue angioplasty yield a high rate of acute TIMI 3 patency rate early after thrombolysis and hospital admission. A randomized, prospective comparison between these 2 reperfusion strategies may be now warranted.

Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens. ALKK-Study Group.

BACKGROUND: In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction. METHODS AND RESULTS: The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of 3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76. 3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P =.09), anisoylated plasminogen streptokinase activator complex (59. 5% vs 34.8%, P =.004), and urokinase (62.3% vs 41.7%, P =.03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy. CONCLUSIONS: We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset.