Operative management of non-elective incisional hernia reduces readmission in a national database.

PURPOSE: The aim of this project was to compare patient characteristics, overall efficacy, and readmission events following operative vs non-operative management modalities of non-elective patients presenting with symptomatic incisional hernias. METHODS: This study is a retrospective study of patients and patient demographics that presented as non-elective hospitalizations with symptomatic incisional hernia. Analysis of patients and characteristics utilized the National Readmission Database from 2010 to Q3 of 2015, delineating patient factors and outcomes following operative or non-operative management of hernias. RESULTS: A total of 14,137 patients met inclusion criteria for our study. The majority of patients were treated operatively rather than non-operatively (79 vs. 21%) on their non-elective admission for incisional hernia. Those undergoing surgical management were younger (56 vs 61 years, p < 0.01), we more often of male gender (69 vs 64%, p < 0.01), and had fewer comorbidities (1.92 vs 2.97, p < 0.01) and chronic conditions (0.45 vs 2.68, p < 0.01). Patients managed operatively had a significantly lower readmission rate when compared to patients managed non-operatively (6.6 vs 14.3%, p < 0.01). However, non-operative management was associated with a shorter length of stay (3 vs 4 days, p < 0.01). Of patients who were initially medically managed and had to be readmitted, a further 61% underwent surgical treatment on their readmission. CONCLUSION: In this nationwide study, patients with non-elective admissions for incisional hernia were mostly managed surgically. Those managed operatively had lower rates of readmission when compared to non-operative management. Initial non-operative management was associated with a shorter length of stay and a lower cost to the patient. The results of this study support operative management of symptomatic incisional hernia.

CDC field triage criteria accurately predicts outcomes in high impact trauma.

BACKGROUND: The precision of emergency medical services (EMS) triage criteria dictates whether an injured patient receives appropriate care. The trauma triage protocol is a decision scheme that groups patients into triage categories of major, moderate and minor. We hypothesized that there is a difference between trauma triage category and injury severity score (ISS). METHODS: This retrospective, observational study was conducted to investigate a difference between trauma triage category and ISS. Bivariate analysis was used to test for differences between the subgroup means. The differences between the group means on each measure were analyzed for direction and statistical significance using ANOVA for continuous variables and chi square tests for categorical variables. Logistic and linear regressions were performed to evaluate factors predicting mortality, ICU length of stay. RESULTS: With respect to trauma triage category, our findings indicate that minor and moderate triage categories are similar with respect to ISS, GCS, ICU LOS, hospital LOS, and mortality. However, after excluding for low impact injuries (falls), differences between the minor and moderate categories were evident when comparing to ISS, GCS, ICU LOS, and hospital LOS. Additionally, after excluding for low impact injures, ISS, ICU LOS, and hospital stay were found to correlate well with trauma triage category. CONCLUSIONS: In this retrospective, observational study significant differences were not seen when comparing ISS with the trauma triage categories of moderate and minor during our initial analysis. However, a difference was found after excluding for low impact injuries. These findings suggest that CDC criteria accurately predicts outcomes in high impact trauma.

MicroCT Imaging of Heart Valve Tissue in Fluid.

BACKGROUND: Heart valve computational models require high quality geometric input data, commonly obtained using micro-computed tomography. Whether in the open or closed configuration, most studies utilize dry valves, which poses significant challenges including gravitational and surface tension effects along with desiccation induced mechanical changes. OBJECTIVE: These challenges are overcome by scanning in a stress-free configuration in fluid. Utilizing fluid backgrounds however reduces overall contrast due to the similar density of fluid and tissue. METHODS: The work presented here demonstrates imaging of the mitral valve by utilizing an iodine-based staining solution to improve the contrast of valve tissue against a fluid background and investigates the role of stain time and concentration. RESULTS: It is determined that an Olea europaea oil bath with a relatively high concentration, short stain time approach produces high quality imagery suitable for creating accurate 3D renderings. CONCLUSIONS: Micro-CT scanning of heart valves in fluid is shown to be feasible using iodine staining techniques.

Surgical and non-surgical treatment of inguinal hernia during non-elective admissions in the Nationwide Readmissions Database.

INTRODUCTION: Inguinal hernia repair is one of the most common surgical operations, yet the optimal treatment strategy remains undefined. Treatment of symptomatic inguinal hernias include both surgical and non-surgical approaches. The objective of this study was to determine differences in population, readmission rates, and costs between operative and non-operative approaches for patients admitted non-electively for an inguinal hernia in a national dataset. In addition, we sought to define the baseline characteristics of the two groups and identify potential predictive factors in the non-surgically managed subgroup who were readmitted and treated operatively within 90 days of their first visit. METHODS: This study was a retrospective review of data from the Nationwide Readmissions Database (NRD) from 2010 to 2014. Patients above age 18 who were admitted non-electively for a primary diagnosis of inguinal hernia were included. Patients whose length of stay was < 1% or > 95% percentile or died during the initial visit were excluded. Readmissions within 90 days of the initial visit were flagged. Patients were classified according to initial management strategy: operative versus non-operative. Demographic, clinical, and organizational characteristics were compared between the two cohorts. RESULTS: 14,249 patients met inclusion criteria and were operative (n = 8996, 63.13%) and non-operative (n = 5255, 36.88%) cohorts. When comparing the two groups, readmission rate was lower (0.49% for surgical, 1.78% for non-surgical, p < 0.01), mean length of stay (LOS) longer (3.27 [SE = 0.05] days for surgical, 2.76 days [SE = 0.06] for non-surgical, p < 0.01), and mean total cost higher ($9597 for surgical, $7167 for non-surgical, p < 0.01) in surgically treated patients. The non-surgical population was on average older (63.05 years for surgical, 64.52 years for non-surgical, p < 0.01) with more chronic conditions (3.57 for surgical, 4.05 for non-surgical, p < 0.01). Of the patients initially managed non-surgically, 1.78% (n = 91) were readmitted, and of them, 62.63% (n = 57) were readmitted and managed surgically within 90 days of initial admission (i.e., crossed over from watchful waiting to surgical treatment). Average number of chronic conditions (3.79 versus 4.03, p = 0.74), average number of comorbidities (2.26 versus 2.18, p = 0.87), and average total number of ICD-9 discharge codes (7.44 versus 8.23 p = 0.54 did not differ significantly between the operative versus non-operative sample of the readmitted population. The total cost ($5562.38 versus $8737.28, p = 0.01) was greater in the operative versus non-operative sample. CONCLUSION: Watchful-waiting strategy is the most common treatment approach in patients admitted non-electively for symptomatic inguinal hernia. Readmission after non-elective hospitalization for inguinal hernia is rare, but surgical intervention decreased the likelihood of readmission compared to non-operative management, while also increasing LOS and cost of care. Our data supports a patient centric approach to the management; non-surgical treatment is a viable temporary option even in symptomatic inguinal hernias, while surgical treatment may reduce the likelihood of future readmission.

Hospitalized acute patients with fever and severe infection have lower mortality than patients with hypo- or normothermia: a follow-up study.

OBJECTIVES: Severe infection is a frequent cause of admission to an acute medical unit (AMU). However, not all infected patients present with fever. The aim was to assess differences in 30-day mortality among patients hospitalized with community-acquired severe infection presenting with hypothermia, normothermia or fever. METHODS: A retrospective single-center follow-up at an AMU from August 1, 2009 to August 31, 2011. Patients were included the first time they presented with severe infection within the study period. Temperature was categorized into hypothermia (<36.0ºC), normothermia (36.0ºC-38.0ºC) and fever (>38.0ºC). Severe infection was defined as a discharge diagnosis indicating infection combined with organ failure within the first 24 h after arrival. Multivariable Cox regression analysis was computed to assess the association between temperature and 30-day mortality. RESULTS: A total of 2128 patients with severe infection were included. 3.0% (N = 64) were hypothermic, 57.1% (N = 1216) normothermic and 39.9% (N = 848) had fever at arrival. Crude 30-day mortality was 16.1% (N = 342, 95%CI 14.5-17.7%); 37.5% (N = 24, 95% CI 25.7-50.5%) for hypothermic patients, 18.3% (N = 223, 95%CI 16.2-20.6%) for normothermic patients and 11.2% (N = 95, 95%CI 9.2-13.5%) for patients with fever. Compared to normothermic patients, the adjusted hazard ratio of 30-day mortality among hypothermic patients was 1.62 (95%CI 1.06-2.49) and 0.74 (95%CI 0.58-0.94) among patients with fever. CONCLUSIONS: Over half of the patients admitted to an AMU with severe infection were normothermic at arrival. Hypothermia was associated with an increased risk of short-term mortality, whereas patients with fever were associated with a lower risk compared to those with normothermia.

Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases.

The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (RYR2) gene in a cohort of persons aged 0-40 years who died of sudden unexpected death syndrome (SUD), including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the RYR2 gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the RYR2 gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene RYR2 than in a previously reported cohort of SIDS (9.4% vs. 1-2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.

Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms.

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.

Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy.

The aim of this investigation was to identify and characterise pathogenic mutations in a sudden cardiac death (SCD) cohort suspected of cardiomyopathy in persons aged 0-40 years. The study material for the genetic screening of cardiomyopathies consisted of 41 cases and was selected from the case database at the Institute of Forensic Medicine. Mutational screening by DNA sequencing was performed to detect mutations in DNA samples from deceased persons suspected of suffering from hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricle cardiomyopathy (ARVC). A total of 9 of the examined 41 cases had a rare sequence variant in the MYBPC3, MYH7, LMNA, PKP2 or TMEM43 genes, of which 4 cases (9.8%) were presumed to be pathogenic mutations. The presumed pathogenic mutations were distributed with one case of suspected HCM and DCM (MYH7; p.R442H), one case of suspected DCM (LMNA; p.R471H), and two cases of suspected ARVC (PKP2; p.R79X and LMNA; p.R644C). The presented data adds important information on the genetic elements of SCD in the young, and calls for expert pathological evaluation and molecular autopsy in the post-mortem examination of SCD victims with structural anomalies of the heart.

Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma.

BACKGROUND: Low serum sodium has recently been associated with poor survival in localised renal cell carcinoma (RCC). We now show the prognostic effect of serum sodium in patients with metastatic RCC (mRCC). METHODS: Cohort A comprised 120 consecutive patients with mRCC receiving subcutaneous, low-dose interleukin-2 and interferon-alpha. Hyponatremia was assessed in univariate and multivariate analyses. An independent cohort of another 120 patients with mRCC was used for validation (cohort B). RESULTS: In cohort A, estimated 5-year survival was 15% and median survival was 15.1 months. Serum sodium ranged between 126 and 144 mM. Twenty-four patients (20%) had serum sodium levels below normal range (<136 mM). In multivariate analysis, significant independent risk factors for short survival were low serum sodium (P=0.014), high neutrophils (P=0.018), lactate dehydrogenase >1.5 upper normal level (P=0.002), and number of metastatic sites (+3) (P=0.003). In cohort B, serum sodium ranged between 128 and 146 mM. Seventeen patients (14%) had sodium levels below normal range. In multivariate analysis, serum sodium was validated as an independent prognostic factor (P=0.001). A significant association between lack of response and hyponatremia was observed in both cohorts (P=0.003 and P=0.02, respectively). CONCLUSION: Low serum sodium is a new, validated, independent prognostic, and predictive factor in patients with mRCC.

Does dissatisfaction with psychosocial work climate predict depressive, anxiety and substance abuse disorders? A prospective study of Danish public service employees.

BACKGROUND: The aim of this study was to examine if dissatisfaction with psychosocial work climate predicts psychiatrically diagnosed depressive, anxiety and substance abuse disorders. METHODS: In Aarhus County, Denmark, 13 423 public service employees at 683 workplace units answered a questionnaire survey assessing psychosocial work environment. An average workplace unit score of overall satisfaction with psychosocial working conditions, rated on a scale from 0-10 with 10 being most satisfied, was computed and assigned to the individual employees at each work unit. Aggregated satisfaction scores were divided into three levels, according to the 25-75 percentiles. Data on hospitalisations and outpatient treatments for depressive, anxiety and substance abuse disorders was obtained from the Danish Central Psychiatric Research Register. HRs and 95% CIs were computed for first onset of studied disorders, starting from the baseline survey at 1 January 2002 through to 30 April 2008. Risk estimates were adjusted for sociodemographic variables. RESULTS: A low satisfaction with psychosocial working conditions was associated with an increased risk of any mental health disorder, HR(adj) 1.71, 95% CI 1.04 to 2.82. The lower the satisfaction level, the higher was the risk of mental health disorders. Moreover, substance abuse disorders were more frequent among men dissatisfied with work climate, HR(adj) 3.53, 95% CI 1.55 to 8.03. CONCLUSION: Working in a dissatisfying psychosocial environment increases the risk of subsequent mental health disorders. Randomised, controlled intervention trials may help in resolving whether this association is causal.

Natural background and anthropogenic inputs of polycyclic aromatic hydrocarbons (PAH) in sediments of South-Western Barents Sea.

Polycyclic aromatic hydrocarbons (PAH) were measured in sediment cores from 13 locations in South-Western Barents Sea as part of a detailed study of the Norwegian seabed under the MAREANO program. The generally low PAH levels found, an average around 200 ng g(-1) dry weight for sum PAH, indicate low inputs of petroleum hydrocarbons to the marine environment in the area. Differences in PAH composition and various PAH ratios indicate a natural, mostly petrogenic origin of PAH in sediments from the open sea locations, while the fjord locations show higher pyrogenic PAH contents with an increase towards upper sediment layers, indicating low inputs from human activities. Petrogenic PAH levels increase in deeper sediments at open sea locations, also when normalised to total organic carbon (TOC) contents, suggesting natural leakages of oil-related hydrocarbons in the area.

Prophylactic cavotricuspid isthmus block during atrial fibrillation ablation in patients without atrial flutter: a randomised controlled trial.

OBJECTIVES: This randomised trial evaluated if patients with atrial fibrillation (AF) and no history of atrial flutter (AFL) had any benefit of prophylactic cavotricuspid isthmus block (CTIB) in addition to circumferential pulmonary vein ablation (CPVA). METHODS: 149 patients with AF (54% paroxysmal) were randomised to CPVA and CTIB (group CTIB+, n = 73) or CPVA alone (group CTIB-, n = 76). Patients were followed for 12 months with repetitive 7-day Holter monitoring after 3, 6 and 12 months. RESULTS: Six patients (4%) had cardiac tamponade, and one patient had a stroke. No difference was found in the cumulative AFL-free rate between the two treatment groups (CTIB+: 88% vs CTIB-: 84%, hazard ratio (HR) 0.80, 95% CI (0.34 to 1.90), p = 0.61). There was no difference in the cumulative AF-free rate between the groups (CTIB+: 34% vs CTIB-: 32%, HR 0.93, 95% CI (0.63 to 1.38), p = 0.71). Overall, 33% of the patients were free of AF after a single procedure. Including reprocedures, a complete or partial beneficial effect was noted in 62% of the patients at 12 months. At 12-month follow-up, 24 (50%) patients with documented AF or AFL in the Holter recordings were asymptomatic. CONCLUSIONS: It was not possible to demonstrate any beneficial effect of CTIB in addition to CPVA with regard to AFL or AF recurrences during follow-up. Repetitive long-term Holter monitoring demonstrated a 33% rate of freedom from AF during a 1-year follow-up. Including additional CPVA procedures, a clinical effect was noted in 62% of the patients at 12 months. Patients with AF or AFL recurrences were often asymptomatic.

The platelet polymorphism PlA2 is a genetic risk factor for myocardial infarction.

OBJECTIVES: Platelet glycoprotein (GP) receptor IIb/IIIa plays a key role in the development of myocardial infarction (MI), and Pl(A2) is a polymorphism in the gene encoding this receptor. The prevalence of Pl(A2) shows pronounced geographical variation and has to our knowledge not been presented for a Scandinavian population before. Platelets from Pl(A2)-positive individuals show increased aggregability compared with platelets from Pl(A2)-negative individuals, and Pl(A2) genotypes might be associated with MI. The purpose of this study was to investigate the relation between the Pl(A2) polymorphism and MI in a large Scandinavian population. DESIGN: Case-control study. We included patients with angiographically verified CAD with and without previous MI and a group of healthy individuals matched for age, race, and sex. RESULTS: We studied the frequency of Pl(A2) in 1191 healthy individuals and 1019 patients with coronary artery disease (CAD). Amongst these patients, 529 subjects had suffered an MI previously. Pl(A2) was present in 28% of healthy individuals, 28% of patients with CAD but no MI, and in 35% of patients with CAD and MI. The difference between healthy individuals and MI patients was significant (P = 0.002). Furthermore, a graded relationship between the number of Pl(A2) alleles and the risk of MI was seen (P = 0.011). Associations between Pl(A2) and traditional cardiovascular risk factors as well as mean platelet volume were investigated. We found a significant interaction between Pl(A2) and serum cholesterol. CONCLUSION: In our Scandinavian study population the common platelet polymorphism Pl(A2) is significantly associated with an increased risk of MI, but not of CAD. Clinically, typing for Pl(A2) might have implications for antiplatelet therapy of patients with MI.

LDL receptor mutation genotype and vascular disease phenotype in heterozygous familial hypercholesterolaemia.

Patients with homozygous familial hypercholesterolaemia (FH) caused by receptor-negative, low-density lipoprotein (LDL) receptor gene mutations have higher concentrations of LDL-cholesterol in plasma and earlier onset of cardiovascular disease (CVD) than patients homozygous for receptor-defective, LDL receptor mutations. In contrast, it is uncertain whether the severity of atherosclerotic disease differs in heterozygous FH caused by receptor-negative and receptor-defective mutations. The present authors investigated the influence of LDL receptor mutation type on the clinical phenotype in 31 patients with heterozygous FH caused by the receptor-negative, Trp23-stop mutation and in 31 patients heterozygous for the receptor defective Trp66-Gly mutation. Untreated levels of plasma LDL-cholesterol and calculated cholesterol-years score did not differ significantly between the two groups of patients. Detection of vascular disease was based on two approaches: (1) measurement of coronary calcification by spiral computed tomography (CT) scanning; and (2) ultrasonic measurement of carotid intima-media thickness (IMT). Age was significantly correlated to the presence of coronary calcification, but controlling for relevant cofactors, there was no evidence that the receptor-negative mutation caused more calcification than the receptor-defective mutation. Furthermore, carotid IMT was significantly influenced by plasma concentrations of Lp(a) and triglycerides, as well as by age, sex and smoking status, but again, there was no statistically significant effect of LDL receptor gene mutational type. The similarity in vascular phenotypes was probably caused by a similar life-long burden of LDL-cholesterol in the two groups of patients.

Four-strand hamstring tendon autograft compared with patellar tendon-bone autograft for anterior cruciate ligament reconstruction. A randomized study with two-year follow-up.

Seventy-two patients with subacute or chronic rupture of the anterior cruciate ligament were randomly assigned to autograft reconstruction with four-strand gracilis and semitendinosus tendon (N = 37) or with patellar tendon-bone (N = 35) from the ipsilateral side. The groups were similar in terms of age, sex, level of activity, degree of laxity, meniscal lesions found surgically, and rehabilitation program. The follow-up was performed at another hospital by independent observers after 6, 12, and 24 months. Sixty-one patients (32 with hamstring tendon grafts and 29 with patellar tendon grafts) complied with the follow-up routine for the full 24 months. No differences were found between the groups with respect to Cincinnati functional score, KT-1000 arthrometer measurements, or stairs hopple test results. The subjective result and the single-legged hop test result were better for the hamstring tendon group after 6 and 12 months, but no differences were found after 24 months. The hamstring tendon group showed better isokinetic knee extension strength than did the patellar tendon group after 6 months, but not after 12 and 24 months. There was a significant weakness in isokinetic knee flexion strength among the hamstring tendon group. Anterior knee pain was not significantly different between the groups, but kneeling pain was significantly less common in the hamstring tendon group after 24 months.

Impact of acute biventricular pacing on left ventricular performance and volumes in patients with severe heart failure. A tissue doppler and three-dimensional echocardiographic study.

OBJECTIVES: We used tissue velocity imaging (TVI) and three-dimensional echocardiography to evaluate the effect of acute biventricular pacing on left ventricular (LV) performance and volumes in patients with severe heart failure and bundle branch block. BACKGROUND: Biventricular pacing causes acute hemodynamic improvement in patients with severe heart failure, and QRS duration has been used as a predictor of improved resynchronization. Tissue velocity has the potential of demonstrating the degree of LV resynchronization and three-dimensional echocardiography enables accurate quantitation of LV volumes and function. METHODS: TVI and three-dimensional echocardiography were performed during sinus rhythm and biventricular pacing in 25 consecutive patients with severe heart failure. RESULTS: Biventricular pacing significantly improved the extent of contracting myocardium in synchrony by 15.4% and the duration of contraction synchrony by 17% (p < 0.05 for both). Furthermore, end-diastolic and end-systolic volumes decreased by 7 +/- 4.5% and 13 +/- 6% (p < 0.01) and ejection fraction increased by 22.8 +/- 9% (p < 0.01). Baseline duration of QRS and the preejection period as well as the extent of myocardium with asynchronous contraction measured by TVI predicted pacing efficacy. In multivariate analysis, only the extent of myocardium with asynchronous contraction at the LV base predicted biventricular pacing efficacy. CONCLUSION: Biventricular pacing improves LV systolic performance and reduces LV volumes during short-term treatment. TVI provides important pathophysiological information on the degree of LV resynchronization and may contribute to improved patient selection.

Incomplete thromboxane inhibition with 100 mg of intravenous acetylsalicylic acid in patients with acute ST elevation myocardial infarction: a placebo-controlled pilot trial.

BACKGROUND: Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A(2) (TXA(2)) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA(2) synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA(2) synthesis in AMI patients treated with streptokinase. METHODS AND RESULTS: Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB(2) and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB(2) after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA(2) production achieved. No significant change in bleeding time could be demonstrated. CONCLUSION: Intravenous ASA in a dosage of 100 mg did not completely prevent TXA(2) production in AMI patients treated with streptokinase. This may be due to synthesis of TXA(2) by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

LDL-receptor gene mutations and the hypocholesterolemic response to statin therapy.

Studies of the cholesterol lowering effect of statin therapy as a function of low-density lipoprotein (LDL)-receptor mutation type have not produced a clear picture, possibly because they included patients with several different kinds of LDL-receptor mutations. We studied the response to treatment with fluvastatin in 28 patients with heterozygous familial hypercholesterolemia as a result of a receptor-negative mutation (Trp23-stop) and in 30 patients with a receptor-binding defective mutation (Trp66-Gly) to test the hypothesis that response to treatment depends on the type of mutation. Patients were randomized to 12 weeks of treatment with fluvastatin 40 mg daily and 12 weeks of placebo treatment, preceded by a placebo run-in period of 8 weeks in a double-blind, cross-over design. Untreated plasma concentrations of lipids and lipoproteins were similar in the two groups of patients. Plasma cholesterol and LDL cholesterol response to therapy tended to be less marked in receptor-binding defective patients, but the differences were not statistically significant. A tabulation of the results of the present and earlier studies suggests that differences in treatment response as an apparent function of LDL-receptor gene mutational type occur mainly in populations with recent genetic admixture (<400 years). In such populations, persons with the same mutation in the LDL-receptor gene are more likely to share other but undetermined genetic variations affecting the pharmacology of statins.