Is the surgical repair of unruptured atherosclerotic aneurysms at a higher risk of intraoperative ischemia?

Background

The incidence of ischemia might be increased in the surgical repair of atherosclerotic unruptured aneurysms compared to non-atherosclerotic aneurysms. The atherosclerotic wall might increase the occurrence of thrombembolic events or its rigidity might endanger the occlusion of perforators within the aneurysm vicinity.

Methods

87 patients (53 patients without and 34 patients with atherosclerotic unruptured aneurysms, 50.5 ± 9.7 years) were analyzed for severity of atherosclerosis within the aneurysm and the aneurysm bearing vessel, surgical maneuvers, intraoperative alterations in evoked potentials and clinical and neuroradiological results.

Results

Temporary vessel occlusion (25% vs. 50%, p = 0.021), repositioning of a permanent clip (21% vs. 56%, p = 0.001) and aneurysm remnants (2% vs. 18%, p = 0.012) occurred more often in patients with atherosclerotic aneurysms. At 6 months, 3/34 patients with atherosclerosis (8.8%) had an unfavorable outcome, all patients without atherosclerosis had a favorable outcome (p = 0.056).

Conclusion

The surgical repair of unruptured aneurysms is safe but patients with atherosclerotic altered vessels and aneurysms accounted to a minor increase in unfavorable outcome and an increased risk of morbidity at 6 months postoperatively. This factor should be taken into consideration when performing surgery of atherosclerotic, unruptured aneurysms.     

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

Objective

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Method

Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

Results

We observed no genome-wide statistically significant findings, but a SNP in a K⁺-dependent Na⁺/Ca²⁺ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

Conclusions

The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.     

Epilepsy surgery for insular lesions

Objective

Due to the proximity of eloquent areas of the brain, the surgical treatment of insular lesions causing refractory epilepsy is considered difficult. We report here on our experience in this field.

Methods

We identified 24 patients (age: 1-62 years, mean 27) who underwent epilepsy surgery for an insular lesion from the epilepsy surgery data bank. We analyzed the preoperative diagnostics, surgical strategy and postoperative follow-up (duration: 12-168 months, mean 37.5) for functional morbidity and seizure outcome.

Results

Eight patients had strictly insular lesions while, in 16 cases, the lesion extended into the frontal (n = 3) or temporal (n = 8) lobe, or was multilobar (n = 5). Sixteen resections (66.7%) were right-sided. Six patients required invasive EEG with implanted electrodes, while three had the aid of intraoperative electrocorticography. In 12 patients, continuous electrophysiological monitoring was used intraoperatively (phase reversal, motor evoked potentials) and, in seven, neuronavigation. In seven patients, only subtotal resection of the insular lesion was possible due to involvement of eloquent areas, and two patients required repeat surgery to complete the resection. Thirteen patients had glial/glioneural tumours (WHO grades I-III), 11 from non-neoplastic lesions. Postoperatively, two patients (8.3%) had a transient neurological deficit (hemiparesis and dysphasia, respectively). One patient had permanent hemihypaesthesia, another had permanent deterioration of preexistent hemiparesis and two had hemianopia as calculated deficit (16.6% rate of mild permanent morbidity). According to the International League against Epilepsy (ILAE) classification, 15 patients were totally seizure-free (62.5%, ILAE 1) and 79.2% had a satisfactory seizure outcome (ILAE 1-3).

Conclusion

In selected patients, an individually tailored lesionectomy of insular lesions can be performed, with acceptable safety, to provide a high rate of satisfactory seizure relief. Indeed, even subtotal resection can result in effective seizure control.     

Enhanced platelet reactivity and thrombosis in Apoe-/- mice exposed to cigarette smoke is attenuated by P2Y12 antagonism

Introduction

Smoking increases the risk of acute arterial thrombosis, including myocardial infarction, likely due to multi-factorial effects on the vasculature. Heightened platelet reactivity may be among the adverse effects of smoke exposure.

Methods

To examine the effects of smoke exposure on platelet function in an atherosclerotic environment, Apoe-deficient female mice, maintained on a Western diet, were exposed (4 hrs/d, 5d/wk) to sidestream cigarette smoke in a whole-body exposure chamber for12 weeks. A separate group of wild type C57BL/6 J mice were also exposed to smoke in an identical fashion.

Results

In comparison to control Apoe-/- mice exposed to filtered ambient air, smoke-exposed Apoe-/- mice displayed a 1.8 ± 0.3 fold enhanced ADP-induced fibrinogen binding ex vivo (P < 0.001) and had a shorter time to thrombotic occlusion following ferric chloride injury of the carotid artery (median time to thrombosis of 8 vs. 13 min; P = 0.015). Administration of the direct-acting P2Y12 antagonist cangrelor blunted ex vivo fibrinogen binding and attenuated thrombosis (median time 20 min) in Apoe-/- mice exposed to sidestream smoke. The effects of smoke exposure required a proatherosclerotic background, as wild-type C57Bl/6 J mice exposed to smoke displayed similar fibrinogen binding and thrombotic occlusion times as did control mice.

Conclusions

Our results demonstrate that exposure to smoke heightens platelet reactivity and thrombosis in Apoe-/- mice and implicate signaling through platelet P2Y12 receptor as a mediator of the adverse consequence of smoke exposure. These results may partially explain the recent observations that smokers derive greater clinical benefit from the P2Y12 antagonist clopidogrel than do non-smokers.     

Factor XII Ofunato: Lys346Asn mutation associated with blood coagulation factor XII deficiency causes impaired secretion through a proteasome-mediated degradation

Introduction

Congenital blood coagulation factor XII (FXII) deficiency is a rare coagulation disease and an autosomal recessive trait. It is found by chance in many cases. We identified a novel mutation (Lys346Asn) in the FXII gene of a patient with FXII deficiency, designated as Factor XII Ofunato.

Methods

The proband was a 75-year-old Japanese woman with a prolonged activated partial thromboplastin time (52.8 s). The FXII activity and antigen were greatly reduced (activity, 5%; antigen, 4.5%). We analyzed FXII gene of this patient using a direct sequencing method and characterized mutant FXII through in vitro expression studies.

Results

Sequence analysis of the FXII gene revealed a G → C point mutation at nucleotide 9845, resulting in Lys346 (AAG) → Asn (AAC) replacement in the catalytic domain. Expression studies in Chinese hamster ovary cells demonstrated that mutant FXII (346 N-FXII) showed a lower level of accumulation in the cells than wild-type. Secretion of 346 N-FXII was greatly reduced in culture medium. We also investigated mRNA expression levels of wild-type and 346 N-FXII in transfected cells using quantitative RT-PCR. Both mRNA expressions were equivalent levels. Pulse-chase experiments showed that 346 N-FXII was extensively degraded intracellularly compared to wild-type. Using membrane-permeable inhibitors, we observed that degradation occurred in the pre-Golgi compartment and that proteasome apparently plays a central role in this process.

Conclusions

These results show that most 346 N-FXII is degraded intracellularly through endoplasmic reticulum-associated degradation as the protein quality control system, resulting in an insufficient secretion phenotype.     

Sleep deprivation and accidental fall risk in children

Objectives

To look for an association between sleep deprivation and risk of accidental falls (AF) in children.

Methods

A questionnaire was applied to two groups of children aged 1-14 years, encompassing children observed in an emergency room for AF (G1) and children attending health care visits (HV) (G2). Collected data included demographic characteristics, medical history, previous week’s sleep pattern (PWSP), sleep duration and sleep pattern in the preceding 24 h, mechanism of fall, and injury severity. Exclusion criteria: acute or chronic disease or exposure to drugs interfering with sleep. Statistical analyses included Fisher’s exact test, Pearson Chi-square, Fisher-Freeman-Halton test, T and Mann-Whitney tests for independent samples, and multivariate logistic regression (α = 5%).

Results

We obtained 1756 questionnaires in G1 and 277 in G2. Of those, 834 in G1 and 267 in G2 were analyzed. We found an increased risk of AF in boys (OR 1.6; 95% CI 1.2-2.4). After controlling for age, gender, summer holidays, parental education and profession, lack of naps and PWSP were associated with increased risk (OR 2.1; 95% CI 1.3-3.3 and OR 2.7; 95% CI 1.2-6.1). In 3-5 year-old children there was an association between AF and a shorter than usual sleep duration in the previous 24 h (p = 0.02).

Conclusions

To our knowledge, our study is the largest so far to assess the association between sleep deprivation and childhood injury. It evidences a protective effect of naps in children. Sleep duration of less than 8 h increases risk of AF. Pre-schoolers may be particularly susceptible to sleep deprivation.     

Impaired spontaneous thrombolytic activity measured by global thrombosis test in males with metabolic syndrome

Introduction

In patients with metabolic syndrome (MetS), activity of the fibrinolytic system is generally surmised to be decreased through increased plasminogen activator inhibitor-1 (PAI-1) generation. However, there have been no detailed reports describing whether the clot lysis activity is more dominant than increased clot formation activity for production of the thrombotic state in MetS.

Methods

The global thrombosis test (GTT) is a novel method designed to test both clot formation and clot lysis activities under physiological conditions by using non-anticoagulated blood samples in vitro. We used the GTT to examine the thrombotic or thrombolytic states in males with MetS.

Results

Lysis time, which reflects spontaneous clot lysis activity, was significantly longer in MetS subjects (median, 1494 s; range, 865-3596 s; n = 30) than in control subjects (median 1246 s; range, 667-2239 s; n = 53). There was no significant difference between the two groups in occlusion time, which reflects platelet function. The mean level of PAI-1 was significantly higher in MetS subjects than in controls (mean ± SE, 8.7 ± 1.1 and 5.0 ± 0.5 ng/mL, respectively). PAI-1 level and lysis time were significantly correlated (r = 0.400, P < 0.01).

Conclusion

These results suggest that male patients with MetS are more likely than controls to experience a thrombotic state through decreased fibrinolytic activity due to increased PAI-1 generation, and that the GTT is useful for evaluating fibrinolytic activity in vitro.     

Lower tissue factor inhibition in patients with ST segment elevation than in patients with non ST elevation acute myocardial infarction

Introduction

Mechanisms to explain the different course of coronary thrombosis between ST elevation myocardial infarction (STEMI) and non-STEMI patients remain poorly defined. We hypothesize, however, that STEMI patients may present lower tissue factor plasma inhibition to partly account for their more persistent coronary thrombotic occlusion.

Materials and Methods

Total (t-TFPI ) and free tissue factor plasma inhibitor (f-TFPI), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), and fibrinogen were measured on admission and at 3 and 6 months in patients with a first STEMI (n:69) or non-STEMI (n:60). C reactive protein (CRP) was also measured on admission and at 3 months.

Results

STEMI patients showed lower admission levels of t-TFPI (p = 0.001), f-TFPI (p = 0.030) and fibrinogen (p = 0.022), and higher vWF levels (p = 0.005) than non-STEMI whereas TAT, PAI and CRP levels were comparable. At 3 and 6 months VWF, t-TFPI, f-TFPI, and TAT levels declined significantly in the 2 groups (p = 0.002) reaching similar values. CRP levels also declined at 3 months (p = 0.002). Moreover, the rate of cardiac mortality, non fatal MI or stroke during a 6 year follow-up were unrelated to admission coagulation parameters.

Conclusions

The lower inhibition of tissue factor and greater endothelial dysfunction in STEMI than in non-STEMI patients may enhance thrombosis at the culprit lesion and adjacent coronary plaques, and hence, account at least in part for their different pathophysiology. This condition, however, is limited to the acute phase.     

Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study

Background

Enoxaparin sodium (enoxaparin) is used worldwide for the prevention of venous thromboembolism (VTE). Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and its preventive use in Japanese patients has yet to be established. To address this, we evaluated the efficacy and safety of postoperative enoxaparin in Japanese patients undergoing surgery for abdominal cancer.

Methods

This multicenter, open-label study randomized 151 Japanese patients undergoing curative surgery for abdominal cancer to enoxaparin 20 mg twice daily for 14 days, started 24-36 hours after surgery (n = 113) or intermittent pneumatic compression (IPC) as a reference (n = 38). IPC was performed at least once in both groups between randomization and surgery. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population. The primary safety outcome was the incidence of any bleeding during treatment and follow-up.

Results

Incidence of VTE was 1.2% (95% CI, 0.03-6.53%) (1/83 patients) in the enoxaparin group and 19.4% (95% CI, 7.45-37.47%) (6/31 patients) in the IPC group. In the safety population, 10/109 patients in the enoxaparin group (9.2%; 95% CI, 4.49-16.23%) and 3/38 patients in the IPC group (7.9%; 95% CI, 1.66-21.38%) experienced a bleeding event. There were no cases of fatal bleeding or bleeding into any critical organ.

Conclusions

These favorable efficacy and safety data support the use of enoxaparin (20 mg twice daily for 14 days started 24-36 hours after surgery) in Japanese patients undergoing abdominal or pelvic cancer surgery.     

Weight gain and ghrelin level after olanzapine monotherapy

Background

The present study aimed to explore the association between weight gain and ghrelin among schizophrenic patients under olanzapine treatment. The relationships among weight gain and adiponectin, fasting glucose, and lipid profile were also investigated.

Methods

This case-control study recruited 66 schizophrenic patients from the Chung Shan Medical University Hospital in central Taiwan. All of them were undergoing olanzapine monotherapy and were categorized into weight gain (WG) and non-weight gain (NWG) groups. Subjects in the control group (CG) were recruited from a healthy community population based on a health survey (n = 119). Multivariate logistic regression was used to explore the association of ghrelin with weight gain.

Results

The 66 schizophrenic patients had a mean age of 36.3 ± 9.6 years, with 50% females. They received olanzapine treatment for a mean period of 8.3 ± 7.5 years. The control group had a mean age of 38.9 ± 9.3 years and 52.9% were females. Comparing fasting serum ghrelin levels, the WG group had the lowest mean value (822.3 ± 253.1 pg/ml) while the control group had the highest mean value (1261.2 ± 1639.7 pg/ml), with a significant difference between the two (p = 0.01). In contrast, there was no difference in adiponectin levels among the three groups. The WG and NWG groups had higher diastolic blood pressure than the control group, but systolic blood pressure was the same in all three groups. There was no difference in the total cholesterol level although the WG and NWG groups had higher triglyceride (TG) and glucose levels than the control group.

Conclusions

Weight gain after olanzapine treatment is associated with lower ghrelin level. Olanzapine is linked to elevated diastolic pressure, TG, and glucose, regardless of the weight gain.     

Incidence and characteristics of asymptomatic distal deep vein thrombosis unexpectedly found at admission in an Internal Medicine setting

Introduction

Lower limb deep vein thrombosis (DVT) is the most frequent clinical manifestation of venous thromboembolism (VTE) and can involve proximal or distal veins. Distal DVT (dDVT) is often asymptomatic and data about its incidence and prognosis are scanty, especially in high risk medical inpatients. Therefore, no consensus exists on the value of detecting and treating dDVTs. Aim of study was to evaluate incidence and characteristics of asymptomatic isolated dDVT at admission in an Internal Medicine department.

Materials and methods

Consecutive patients hospitalized for acute medical illnesses, in whom VTE was not the admission diagnosis, underwent Doppler Ultrasonography. For all patients with dDVT standard treatment with therapeutic doses of low molecular weight heparin or fondaparinux was proposed. Follow-up visits were scheduled at 1, 6 and 12 weeks.

Results

One-hundred-fifty-four patients were enrolled. In 4.5% a proximal DVT and in 16.2% an asymptomatic dDVT were found. Female sex, elevated age and renal and electrolyte abnormalities were significantly associated to dDVT (p = 0.014, p = 0.009 and p = 0.046, respectively). Only low degree of mobility (LDM) was independently associated to dDVT [OR 7.97 (95%CI 2.42-26.27), p = 0.001)]. A high mortality rate, not for VTE-related causes, was found, especially in the first week, among dDVT patients.

Conclusions

We found a high incidence of clinically silent dDVTs. LDM evaluation could be useful to select patients at high risk in whom to perform a search for dDVT.     

Venous thromboembolism risk assessment and thromboprophylaxis among hospitalized acute medical patients in China - the RAMP study

Background

In developed countries, hospitalized patients with acute medical conditions are at significant risk for venous thromboembolism (VTE). Little is known about VTE risk and prophylaxis practices in China.

Objective

To determine the VTE risk and the frequency of recommended VTE prophylaxis in hospitalized Chinese patients with acute medical conditions.

Methods

Multi-center, cross-sectional, observational study. Eligibility criteria: ≥ 30 years, admitted to an intensive care unit (ICU)/coronary care unit (CCU) for acute medical illness, had ≥ 1 VTE risk factor/1 disease that predisposes to VTE, and provided informed consent. We used 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines to assess VTE risk and the frequency of recommended VTE prophylaxis.

Results

1247 patients from 19 hospitals in 11 cities across 11 provinces of China were enrolled from July 2007 to June 2008. 57.3% patients had > 2 VTE risk factors. Only 20.2% received ACCP-recommended VTE prophylaxis (CCU patients: 22.7%, ICU patients: 16.9%, p = 0.0117).

Limitations

Excluding some patients with VTE risk factors did not allow assessment of the prevalence of VTE risk in the acute hospital-care setting. We could not determine whether the duration of prophylaxis complied with the ACCP recommendations. Our results may not be representative of hospitals in small cities/rural areas in China.

Conclusions

The prevalence of VTE risk factors in Chinese patients was similar to that in developed countries; however, only a small proportion of eligible patients received the recommended VTE prophylaxis. Our findings highlight the need for dissemination and implementation of appropriate VTE prophylaxis guidelines in China.     

Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity

Introduction

Elevated levels of tissue factor positive (TF⁺) microparticles (MPs) are observed in plasma from a variety of patients with an increased risk of thrombosis. We and others have described the measurement of TF activity in MPs isolated from plasma. The aim of this study was to investigate the effects of pre-analytical and analytical variables on TF activity of MPs isolated from blood of healthy volunteers either untreated or treated ex vivo with bacterial lipopolysaccharide.

Materials and methods

We evaluated the following parameters: use of different centrifugation speeds to isolate the MPs; comparison of TF activity of MPs isolated from platelet poor plasma versus platelet free plasma; effect of freeze/thaw on MP TF activity; and comparison of the MP TF activity assay with the measurement of TF protein by ELISA or flow cytometry.

Results

MPs prepared from platelet poor plasma by centrifugation at 20,000 × g or 100,000 × g for 15 minutes had similar levels of TF activity. However, significantly less TF activity was found in MPs isolated from platelet free plasma compared with platelet poor plasma. Interestingly, freeze/thawing of the plasma showed donor to donor variation in MP TF activity, with a moderate increase in some individuals.

Conclusion

TF⁺ MPs can be quantitatively isolated from platelet poor or platelet free plasma by centrifugation at 20,000 × g for 15 minutes. Measurement of MP TF activity in plasma may be used to detect a prothrombotic state in patients with various diseases.     

Influence of blood viscosity to cerebral blood flow in older humans compared to young subjects

Objective

Since blood viscosity (BV) is one of the most important factors determining blood flow, this study aimed to investigate the possible correlation between increased blood viscosity and reduction of regional cerebral blood flow (rCBF) in healthy ageing.

Methods

Male subjects were distributed in two groups: “young”, aged 20-30 (27 volunteers), or “elderly”, aged 60-70 (50 volunteers). Whole blood viscosity was obtained with a Wells-Brookfield Cone/Plate Viscometer. Cerebral blood flow was analysed by means of single photon emission computed tomography (SPECT).

Results

The mean BV values were 3.28 ± 0.43 mPa in the group of young volunteers and 4.33 ± 0.73 mPa in the group of elderly volunteers (t = −6.9, p < 0.0001). The elderly had a lower blood flow than the young in the following regions: bilateral parietal; temporal-parietal and temporal of the left hemisphere. Pearson’s correlation between BV and rCBF showed a good inverse correlation when the BV was above 3.95 ± 0.83 mPa.

Conclusions

Our results point to a close relationship between the two parameters analysed, BV and rCBF. The impairment in rCBF observed in the elderly volunteers might be due to an increase in BV, among other factors.

Significance

These findings suggest interesting possibilities for the treatment/prevention of brain ageing.     

Correlation of clinical findings and results of percutaneous balloon compression for patients with trigeminal neuralgia

Objective

To investigate pain relief and recurrence after percutaneous balloon compression (PBC) and its association with type of pain, prior surgery, or other clinical factors.

Methods

Fifty-nine patients with medically refractory trigeminal pain were enrolled into this study. Patients were divided into those with typical trigeminal neuralgia (TN), and those with other types of trigeminal pain or “atypical pain.” The post-surgical rate of recurrence was estimated by the Kaplan-Meier method. Cox-proportional hazards models were used to investigate associations between patient characteristics and recurrence of pain.

Results

Forty-two patients had TN, 17 patients had atypical pain. At last follow-up, 40 patients had excellent, 9 good, 7 fair and 3 poor pain relief. Recurrence was observed in 35 patients, and was associated with pain type (relative risk (RR) = 2.38, 95% confidence interval (CI): 1.22-4.63, P = 0.011) and pain duration before PBC (RR = 1.33, 95% CI: 1.02-1.72, P = 0.033). Other clinical factors were not significant. Two patients had transient paresis of the sixth cranial nerve, however, there were no permanent post-surgical complications.

Conclusions

Our study demonstrates the safety and efficacy of PBC with 83% of patients being pain free at last follow-up. Patients with atypical pain and longer pre-surgical symptom duration appear to have a higher risk of recurrence. Repeat surgery is just as effective as initial surgery, justification for being conservative in parameter selection at the initial procedure to minimize complications.     

Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain

Background

Platelet glycoprotein VI (GPVI) is elevated in patients with acute coronary syndrome (ACS), stroke and associated with acute coronary events. GPVI may be helpful to distinguish an imminent ACS from non-coronary (NC) causes in patients with chest pain who were transferred to chest pain unit, before the myocardial necrosis is evident with classical biomarkers.

Methods

Based on the findings of our previous studies, we consecutively examined 1004 patients with chest pain in a prospective study design. ACS was found in 416 (41.4%), stable angina pectoris (SAP) in 233 (23.2%), and NC causes of chest pain (hypertension, musculoskeletal disease, pulmonary embolism, myocarditis, cardiophobia) in 355 patients (35.4%). Platelet surface expression of GPVI was measured by flow cytometry.

Results

Patients with ACS showed significantly enhanced GPVI expression levels compared to patients with SAP or NC causes of chest pain (ACSvs.SAP(mean fluorescence intensity (MFI) ± SD):18.9 ± 7.4vs.17.9 ± 9.5;P = 0.028;ACSvs.NC:15.4 ± 6.9;P = 0.002). Elevated GPVI expression was associated with ACS independent of markers of myocardial necrosis like troponin and creatine kinase-MB. Patients with an elevated GPVI expression (MFI ≥ 18.6) had a poorer clinical outcome than patients with baseline GPVI expression in regard to composite cumulative survival that included myocardial infarction, stroke, and cardiovascular death at three months (Log rank;P = 0.025).

Discussion

Platelet GPVI surface expression is enhanced in patients at risk for an ACS and is an early marker for imminent acute coronary events in patients with chest pain.     

Liporetro-D-peptides - a novel class of highly selective thrombin inhibitors

Introduction

Plasma serine protease thrombin plays a key role in coagulation, haemostasis and thromboembolic diseases. Direct thrombin inhibitors could be beneficial for future anticoagulant therapy. We have synthesized and studied liporetro-D-peptides - efficient thrombin inhibitors resistant to enzymatic degradation.

Materials and Methods

Compounds X-D-Arg-D-Phe-OMe, where X = residue of lauric or myristic acid or 9-fluorenylmethoxycarbonyl, have been synthesized by conventional peptide synthesis in solution and their comparative inhibitory analysis in relation to thrombin, factor X, plasmin and trypsin has been conducted.

Results

Modification of the synthetic liporetro-D-peptides with the myristic acid residue was the most successful one. This modification has dramatically increased the inhibition efficacy (Ki = 0,17 μM) and selectivity toward the chosen target enzyme, thrombin, in comparison to factor X, plasmin and trypsin (more than 600, 900, and 5000-fold, respectively).

Conclusions

Our findings establish an important role of the fatty moiety in the structure of peptide inhibitors with regards to their potency and selectivity toward thrombin.     

Efficacy and safety of clopidogrel in children with diarrhea associated hemolytic uremic syndrome

Introduction

Hemolytic uremic syndrome is a thrombotic microangiopathy. Clopidogrel, a recently developed platelet aggregation inhibitor, has not been previously reported as a treatment for this illness. Our study's objective was to explore the efficacy and safety of clopidogrel in children with diarrhea associated hemolytic uremic syndrome.

Materials and Methods

We performed a retrospective chart review of all children (≤ 18 years) hospitalized with diarrhea associated hemolytic uremic syndrome. Outcomes in clopidogrel treated children were described. In subgroup analysis, outcomes were compared to those untreated with platelet aggregation inhibitors.

Results

Of 72 children with diarrhea associated hemolytic uremic syndrome, 88% were treated with platelet aggregation inhibitors (clopidogrel 56%, sulfinpyrazone 19%, dipyridamole 13%). The median age of clopidogrel treated children was 5 years; 40% were male. Initial median hemoglobin, platelet count, and serum creatinine were 10.1 g/dL, 53 × 10³/μL, and 2.3 mg/dL respectively. Clopidogrel (median dose 1 mg/kg/d) was given for a median of 4 days (range 1-15). Other therapies included erythropoietin (98%), red blood cell transfusions (80%), diuretics (58%), anti-hypertensive agents (45%), and dialysis (33%). The median hospital length of stay was 9 days (range 3-26). Three children had bleeding complications (epistaxis/hematemesis). The risk of chronic kidney disease was 5% and death 2.5%. In subgroup analysis, median duration of dialysis was 11 days in thirteen clopidogrel treated children compared to 21 days in five untreated patients (P = 0.04).

Conclusions

Children with diarrhea associated hemolytic uremic syndrome treated with clopidogrel have outcomes comparable to untreated patients. Bleeding complications may occur.     

Extracorporeal cardiopulmonary support may be an efficient rescue of patients after massive pulmonary embolism. An experimental porcine study

Introduction

Treatment of massive pulmonary embolism leading to cardiac arrest is controversial but restitution of circulation within a shorter time is crucial. Cardiopulmonary support and therapeutic hypothermia is an option for cardiac arrest and could be used to treat massive PE. However, hypothermia may influence the effect of the ongoing intrinsic fibrinolysis.

Objectives

To establish a porcine model of massive pulmonary embolism, to show that cardiopulmonary support can rescue pigs with massive pulmonary embolism and to examine the effect of hypothermia on fibrinolysis.

Methods

Pigs ~ 80 kg were anesthetised and prepared for cardiopulmonary support. Repetitive injections of preformed blood thrombi into the right atrium were done until cardiac arrest. Cardiopulmonary support was established and eighteen pigs were randomised into 3 groups: Normothermia (38-39 °C); hypothermia (33-34 °C); or medication with recombinant tissue plasminogen activator. After three hours the pigs were weaned from cardiopulmonary support, and after 15 minutes with spontaneous circulation assassinated and autopsied. Remaining thrombi in the lungs were weighed.

Results

The development of fatal pulmonary embolism was highly reproducible. All 18 pigs could be weaned from cardiopulmonary support and survived more than 15 minutes. The amount of remaining thromboemboli was substantial in all groups and not significantly different between groups. Normothermic group 20.0 ± 2.2 g, Hypothermic group 17.0 ± 3.7 g, and rt-PA group 14.3 ± 3.2 g.

Conclusions

Cardiopulmonary support could rescue pigs with massive pulmonary embolism. Hypothermia did not reduce the emboli but may for other reasons be beneficial. The optimal additional treatment is still unknown but treatment modalities can be tested in this model.     

Patient acceptance of awake craniotomy

Objectives

The aim of this study was to objectively assess the patients’ acceptance for awake craniotomy in a group of neurosurgical patients, who underwent this procedure for removal of lesions in or close to eloquent brain areas.

Patients and methods

Patients acceptance for awake craniotomy under local anesthesia and conscious sedation was assessed by a formal questionnaire (PPP33), initially developed for general surgery patients. The results are compared to a group of patients who had brain surgery under general anesthesia and to previously published data.

Results

The awake craniotomy (AC) group consisted of 37 male and 9 female patients (48 craniotomies) with age ranging from 18 to 71 years. The general anesthesia (GA) group consisted of 26 male and 15 female patients (43 craniotomies) with age ranging from 26 to 83 years. All patients in the study were included in the questionnaire analysis. In comparison to GA the overall PPP33 score for AC was higher (p = 0.07), suggesting better overall acceptance for AC. The subscale scores for AC were also significantly better compared to GA for the two subscales “postoperative pain” (p = 0.02) and “physical disorders” (p = 0.01) and equal for the other 6 subscales. The results of the overall mean score and the scores for the subscales of the PPP33 questionnaire verify good patients’ acceptance for AC.

Conclusion

Previous studies have shown good patients’ acceptance for awake craniotomy, but only a few times using formal approaches. By utilizing a formal questionnaire we could verify good patient acceptance for awake craniotomy for the treatment of brain tumors in or close to eloquent areas. This is a novel approach that substantiates previously published experiences.