Early Fish Oil Supplementation and Organ Failure in Patients With Septic Shock From Abdominal Infections

Background: Fish oil (FO) has immunomodulating effects and may improve organ function and outcome in critically ill patients. This retrospective, propensity‐matched cohort study investigates the effects of early intravenous FO supplementation on organ failure in patients with septic shock from abdominal infection. Methods: A medical database was retrospectively searched for critically ill patients admitted because of septic shock from abdominal infection (n = 194). Demographic, clinical, and laboratory data; FO supplementation (10 g/d) (n = 42); rate, degree, and number of organ failures assessed by the Sequential Organ Failure Assessment (SOFA) score; and secondary outcome variables were recorded. A propensity score‐based model was used to establish 2 comparable groups (FO, n = 29; control, n = 29). Mann‐Whitney rank sum test, Fisher exact test, and logistic regression analyses were used to compare variables between groups. Results: There were no differences in the rate of single organ failures, the maximum SOFA score (median [interquartile range (IQR)], 12 [8‐15] vs 11 [9‐14]; P = .99), or the number of organ failures (median [IQR], 2 [1‐3] vs 2 [1‐3]; P = .54] between patients receiving FO supplementation and those not receiving supplementation. There were no group differences in the maximum C‐reactive protein levels (P = .1), duration of mechanical ventilation (P = .65) or hemofiltration (P = .21), intensive care unit–acquired infections, intensive care unit length of stay (P = .59), and intensive care unit (P = 1) or hospital mortality (P = 1). Conclusions: Early intravenous FO may not decrease the number and degree of organ failures in patients with septic shock from abdominal infection. Future trials are needed before FO supplementation in septic shock from abdominal infection can be recommended.     

Coincidence of two novel arylsulfatase a alleles and mutation 459+1G>A within a family with metachromatic leukodystrophy: Molecular basis of phenotypic heterogeneity

In a family with three siblings, one developed classical late infantile metachromatic leukodystrophy (MLD), fatal at age 5 years, with deficient arylsulfatase A (ARSA) activity and increased galactosylsulfatide (GS) excretion. The two other siblings, apparently healthy at 12½ and 15 years, respectively, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity. The late infantile patient inherited from his mother the frequent 0‐type mutation 459+1G>A, and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG). The two clinically unaffected siblings carried the maternal mutation 459+1G>A and, on their paternal allele, a novel cytosine to thymidine transition at nucleotide 2435 in exon 8, resulting in substitution of alanine 464 by valine (A464V). The fathers genotype thus was 7delG/A464V. Mutation A464V was not found in 18 unrelated MLD patients and 50 controls. A464V, although clearly modifying ARSA and GS levels, apparently bears little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele. Our results demonstrate that in certain genetic conditions MLD‐like ARSA and GS values need not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally similar to A464V might exist which, together with 0‐type mutations, may cause pathological ARSA and GS levels, but not clinical outbreak of the disease. Hum Mutat 13:61–68, 1999. © 1999 Wiley‐Liss, Inc.     

Activated human platelet products induce proarrhythmic effects in ventricular myocytes

Sudden cardiac death remains one of the most prevalent modes of death and is mainly caused by ventricular fibrillation (VF) in the setting of acute ischemia resulting from coronary thrombi. Animal experiments have shown that platelet activation may increase susceptibility of ischemic myocardium to VF, but the mechanism is unknown. In the present study, we evaluated the effects of activated blood platelet products (ABPPs) on electrophysiological properties and intracellular Ca²⁺ (Ca²⁺_i) homeostasis. Platelets were collected from healthy volunteers. After activation, their secreted ABPPs were added to superfusion solutions. Rabbit ventricular myocytes were freshly isolated, and membrane potentials and Ca²⁺_i were recorded using patch-clamp methodology and indo-1 fluorescence measurements, respectively. ABPPs prolonged action potential duration and induced early and delayed afterdepolarizations. ABPPs increased L-type Ca²⁺ current (I_Ca,L) density, but left densities of sodium current, inward rectifier K⁺ current, transient outward K⁺ current, and rapid component of the delayed rectifier K⁺ current unchanged. ABPPs did not affect kinetics or (in)activation properties of membrane currents. ABPPs increased systolic Ca²⁺_i, Ca²⁺_i transient amplitude, and sarcoplasmic reticulum Ca²⁺ content. ABPPs did not affect the Na⁺− Ca²⁺ exchange current (I_NCX) in Ca²⁺-buffered conditions. Products secreted from activated human platelets induce changes in I_Ca,L and Ca²⁺_i, which result in action potential prolongation and the occurrence of early and delayed afterdepolarizations in rabbit myocytes. These changes may trigger and support reentrant arrhythmias in ischemia models of coronary thrombosis.     

Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice

Influenza is controlled by protective titres of neutralizing antibodies, induced with the help of CD4 T-cells, and by antiviral T-cell effector function. Adjuvants are essential for the efficient vaccination of a na?ve population against avian influenza. We evaluated a range of adjuvants for their ability to enhance, in na?ve mice, protective hemagglutination inhibition (HI) titres, which represent the generally accepted correlate of protection, virus-neutralizing titres and T-cell responses to a new generation influenza vaccine produced in cell culture. The selected adjuvants include alum, calcium phosphate (CAP), MF59, the delivery system poly-(lactide co-glycolide) (PLG) and the immune potentiator CpG. MF59 was clearly the most potent single adjuvant and induced significantly enhanced, long-lasting HI and neutralizing titres and T-cell responses in comparison to all alternatives. The combination of alum, MF59, CAP or PLG with CpG generally induced slightly more potent titres. The addition of CpG to MF59 also induced a more potent Th1 cellular immune response, represented by higher IgG2a titres and the induction of a strongly enhanced IFN-gamma response in splenocytes from immunized mice. These observations have significant implications for the development of new and improved flu vaccines against pandemic and inter-pandemic influenza virus strains.     

Impact of different setup approaches in image-guided radiotherapy as primary treatment for prostate cancer

Aim

The goal of this study was to assess the impact of different setup approaches in image-guided radiotherapy (IMRT) of the prostatic gland.

Methods

In all, 28 patients with prostate cancer were enrolled in this study. After the placement of an endorectal balloon, the planning target volume (PTV) was treated to a dose of 70 Gy in 35 fractions. A simultaneously integrated boost (SIB) of 76 Gy (2.17 Gy per fraction and per day) was delivered to a smaller target volume. All patients underwent daily prostate-aligned IGRT by megavoltage CT (MVCT). Retrospectively, three different setup approaches were evaluated by comparison to the prostate alignment: setup by skin alignment, endorectal balloon alignment, and automatic registration by bones.

Results

A total of 2,940 setup deviations were analyzed in 980 fractions. Compared to prostate alignment, skin mark alignment was associated with substantial displacements, which were ≥?8 mm in 13?%, 5?%, and 44?% of all fractions in the lateral, longitudinal, and vertical directions, respectively. Endorectal balloon alignment yielded displacements ≥?8 mm in 3?%, 19?%, and 1?% of all setups; and ≥?3 mm in 27?%, 58?%, and 18?% of all fractions, respectively. For bone matching, the values were 1?%, 1?%, and 2?% and 3?%, 11?%, and 34?%, respectively.

Conclusion

For prostate radiotherapy, setup by skin marks alone is inappropriate for patient positioning due to the fact that, during almost half of the fractions, parts of the prostate would not be targeted successfully with an 8-mm safety margin. Bone matching performs better but not sufficiently for safety margins ≤?3 mm. Endorectal balloon matching can be combined with bone alignment to increase accuracy in the vertical direction when prostate-based setup is not available. Daily prostate alignment remains the gold standard for high-precision radiotherapy with small safety margins.     

Invasive carcinoma of prostate presenting as rectal carcinoma

Prostate carcinoma occasionally can present with rectal obstructive symptoms and an annular constricting lesion of the rectum. Discriminating between primary rectal carcinoma and prostate carcinoma locally invasive to the rectum is of obvious importance because of the different treatments and prognoses. History and physical examination play only a marginal role in differentiating between these two lesions. The diagnosis of prostatic malignancy in patients in this circumstance can be supported by an elevated serum acid phosphatase as well as a bone scan that demonstrates a pelvic/vertebral distribution of bony metastases. The rectal mucosa is usually spared, and a barium enema often will demonstrate tapered margins as opposed to a tumor edge in primary rectal malignancy. Excretory urography often demonstrates hydronephrosis. Rectal biopsy with immunohistochemical staining for prostate specific antigen can direct the origin of a poorly differentiated adenocarcinoma to the prostate. Treatment involves hormonal manipulation with estrogen therapy or orchiectomy. Radiation therapy to the obstructed rectum has provided satisfactory palliation when hormonal manipulation fails.     

Comparison of N-terminal pro-brain natriuretic peptide versus electrophysiologic study for predicting future outcomes in patients with an implantable cardioverter defibrillator after myocardial infarction

The aim of the study was to examine the predictive value of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) versus electrophysiologic study in patients with implantable cardioverter-defibrillators (ICDs) after myocardial infarction (MI). We prospectively studied 99 consecutive patients with a history of MI who underwent ICD implantation for primary or secondary prevention of sudden cardiac death. An electrophysiologic study was performed in all patients. Venous blood samples for NT-pro-BNP measurement were obtained at the beginning of the study. The primary end point was ventricular tachycardia or ventricular fibrillation (VT/VF) and the secondary end point was a composite of death, hospitalization for heart failure, or MI. On multivariate Cox regression analysis, NT-pro-BNP level at or greater than median (497 ng/L) was the only significant predictor for VT/VF occurrence (p = 0.047). Along with amiodarone use (p = 0.001), NT-pro-BNP levels higher than median were also associated with a higher risk of composite clinical events (p = 0.036). Kaplan-Meier analysis showed that patients with NT-pro-BNP level at or greater than median had a higher risk of experiencing VT/VF and composite clinical events than patients with NT-pro-BNP levels less than median (log-rank p <0.05). In conclusion, assay of NT-pro-BNP, which is easy to perform and widely available, is superior to electrophysiologic study for prediction of future outcomes in predominantly secondary prophylactic ICD recipients after MI. In the era of primary prophylactic ICD implantation without preimplantation electrophysiologic study, higher NT-pro-BNP levels might help to improve risk-adjusted concomitant antiarrhythmic therapy and device selection.     

The effect of changes in cardiac frequency on left and right ventricular dP/dt max at different contractile states of the myocardium

Summary In 17 canine heart-lung preparations the dependence of frequency potentiation of the right and left ventricular myocardium on the basic inotropic state of the heart was investigated. The effect of unipolar stimulation of the right atrium on dP/dt max in both ventricles was measured. The aortic pressure was maintained constant.Shortly after isolation of the heart, a stepwise increase of rate from 140 to 200 beats/min only had a very weak influence on left ventricular dP/dt max. With deterioration of the myocardium the frequency potentiation of dP/dt max increased considerably. End-diastolic pressure regularly decreased with rising cardiac frequency. Since the real positive inotropic effect is masked by the concomitant fall in diastolic loading, the end-diastolic pressure was maintained constant in a second group of 8 hearts during rate variation. The most pronounced inotropic effect was now found shortly after isolation of the heart. A rate increase of 30 beats/min resulted in a 20% rise of dP/dt max. The frequency potentiation decreased with deterioration of the heart resulting in a 12% dP/dt max increase at an estimated inotropic state of 50% of control. When the contractile state of the heart was improved above the control state by calcium application the frequency potentiation of the myocardium decreased.In the right ventricle similar results were obtained except for the fact that no significant correlation between the steepness of the frequency characteristics and the contractile state of the heart could be found when the end-diastolic pressure was kept constant.Portions of this study have been presented at the 45th Congress of the German Physiological Society     

Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial

Context  The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists. Objective  To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more. Design, Setting, and Patients  Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups. Intervention  Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175). Main Outcome Measures  Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat). Results  More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank). Conclusions  Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas. Trial Registration  isrctn.org Identifier: ISRCTN34802808