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N Engl J Med 2017;377:2419-2432Background: A small fraction of patients with acute myocardial infarction (5-10%) have cardiogenic shock. These patients have a high baseline mortality. Early revascularization had been established as better than initial stabilization with medical therapy. Many patients with cardiogenic shock due to acute myocardial infarction (AMI) have multivessel disease. The question arises about whether to do culprit-only percutaneous coronary intervention (PCI) or more complete PCI at the time of the initial intervention.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was designed to test the hypothesis that PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, would result in better clinical outcomes than immediate multivessel PCI among patients who have multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock.Patients: The trial enrolled 706 patients with acute myocardial infarction (ST-segment elevation or non-ST-segment elevation) complicated by cardiogenic shock who had multivessel coronary artery disease. Cardiogenic shock was defined as SBP < 90 mmHg for more than 30 minutes or requiring pressors, clinical signs of pulmonary congestion, and signs of organ hypoperfusion (altered mental status, cold/clammy skin, oliguria, or lactate > 2 mmol/L).Exclusion criteria were extensive and designed to exclude patients with extremely poor prognosis: prolonged resuscitation, no intrinsic heart action, fixed dilated pupils, an indication for urgent CABG, a mechanical cause of shock, age > 90 years, massive pulmonary embolism, or severe renal insufficiency at baseline.Baseline Characteristics: The median age was 70 years, and approximately 75% were male. About 63% of patients had three-vessel disease. More than half the patients had ST-segment elevation myocardial infarction (about 62%), and anterior ST-segment elevation MI accounted for approximately 54% of these cases. About 53% of patients required resuscitation before randomization. The median left ventricular ejection fraction was between 30-33%.Procedures: In the culprit-lesion-only PCI group, only the culprit lesion was treated during the initial procedure, with staged revascularization encouraged based on residual ischemic lesions. In the multivessel PCI group, PCI of all major coronary arteries with >70% stenosis was performed, including attempts to recanalize chronic total occlusions. Crossover from the culprit-lesion-only PCI group to the multivessel PCI group occurred in 12.5% of patients, while crossover in the opposite direction happened in 9.4% of patients. The overall dose of contrast material was significantly higher and the duration of fluoroscopy significantly longer in the multivessel PCI group. Other interventional therapeutic measures were allowed, independent of the assigned treatment strategy.Endpoints: The primary endpoint was a composite of death from any cause or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Secondary endpoints included the individual components of the primary endpoint, recurrent myocardial infarction, rehospitalization for heart failure, repeat revascularization, time to hemodynamic stabilization, catecholamine therapy duration, ICU stay duration, and measurements of renal and myocardial injury. Safety end points included bleeding, which was defined as type 2, 3, or 5 on the Bleeding Academic Research Consortium (BARC) scale.Trialists estimated an event rate of the composite primary endpoint of 38% in the culprit-only group vs 50% in the complete group. Using a global type I error level of 0.05, the authors calculated that a sample of 684 patients would give the trial 80% power to rule out the null hypothesis of no difference between the two treatment groups in the event rate for the primary end point.Results: At 30 days, the composite primary endpoint occurred in 45.9% of patients in the culprit-lesion-only PCI group versus 55.4% in the multivessel PCI group (relative risk, 0.83; 95% CI, 0.71 to 0.96; P=0.01). Death occurred in 43.3% of the culprit-lesion-only PCI group versus 51.6% of the multivessel PCI group (relative risk, 0.84; 95% CI, 0.72 to 0.98; P=0.03). The rate of renal-replacement therapy was 11.6% in the culprit-lesion-only PCI group and 16.4% in the multivessel PCI group (relative risk, 0.71; 95% CI, 0.49 to 1.03; P=0.07).Rates of recurrent myocardial infarction, rehospitalization for heart failure, bleeding, and stroke did not differ significantly between groups. Subgroup analyses showed consistent results across all prespecified subgroups. The time to hemodynamic stabilization, the use of catecholamine therapy and the duration of such therapy, the duration of the ICU stay, and the use of mechanical ventilation and the duration of such therapy also did not differ significantly between the two groups.Conclusion: In patients with myocardial infarction and cardiogenic shock, culprit-only PCI was superior to multivessel PCI. Both components of the primary endpoint, death and severe renal failure were lower in the culprit-only arm. The authors and editorialists speculate why these findings contrast with trials in hemodynamically stable myocardial infarction patients, where early multivessel PCI showed benefit over culprit-only PCI.If you accept the thesis that multi-vessel PCI was superior to culprit-only PCI in stable AMI patients, the likely reason for the disparate results are that patients with cardiogenic shock differ substantially from stable patients. The sicker patients with cardiogenic shock benefit from a less-is-more approach where culprit-only PCI reduces treatment harm relative to multivessel PCI.We at CardiologyTrials, however, find the evidence for complete revascularization in stable AMI patients less than clear. The COMPLETE trial found benefit from multivessel PCI over culprit-only, but both composite endpoints were driven largely by non-fatal MI. CV death was not substantially different. The difference in MI could have been related to excluding procedure-related MI.What's more, the FULL-REVASC trial, which also compared culprit-only and multivessel PCI, failed to replicate the COMPLETE trial results. In FULL-REVASC the rates of the composite primary outcome of death, MI or unplanned revascularization were not significantly different. Sadly, FULL-REVASC was stopped early when COMPLETE results were published, which led to a possible loss of power.It's possible, likely even, that the null results of CULPRIT-SHOCK are not really that disparate from prior trials in patients with more stable AMI.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2019;381:1524-1534Background Dual antiplatelet therapy after percutaneous coronary intervention had become a standard of care. Both prasugrel and ticagrelor had been shown to provide more rapid and consistent platelet inhibition than clopidogrel. Randomized controlled trials had shown both drugs were superior to clopidogrel in patients with acute coronary syndromes. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The two drugs have different loading strategies in patients who have acute coronary syndromes without ST-segment elevation. In these patients, ticagrelor is usually administered as pretreatment before diagnostic angiography, but prasugrel is administered only after the coronary anatomy has been assessed by means of diagnostic angiography since no advantage has been observed when prasugrel is used as pretreatment.Before ISAR-REACT 5, there had been no direct comparisons of the two antiplatelet drugs. ISAR-REACT 5 was an investigator-initiated multicenter, non-industry funded RCT to compare the efficacy and safety of the two treatments in patients with acute coronary syndrome. Patients The trial enrolled 4013 patients from 23 centers. Patients were eligible with either STEMI, NSTEMI or unstable angina for which intervention was planned. Exclusion criteria included intolerance of either drugs, history of stroke or intracranial bleeding or any condition that increased the risk of bleeding. Patients could not be on concomitant oral or i.v. therapy with drugs affecting CYP3A4 system. Baseline Characteristics There were 2012 patients assigned to ticagrelor and 2006 patients assigned to prasugrel. The suspected diagnosis at admission was STEMI in 41%, NSTEMI in 46%, and unstable angina in 13% of the patients. The average age was 64 years. Female sex was 24%. Average systolic blood pressure and heart rate was 144 mmHg and 77 bpm. All factors were well balanced. Trial Procedures Therapy with ticagrelor was started at a loading dose of 180 mg and continued at a maintenance dose of 90 mg twice daily. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization. Therapy with prasugrel was started at a loading dose of 60 mg and continued at a maintenance dose of 10 mg once per day. A reduced maintenance dose of 5 mg daily was recommended in patients who were 75 years of age or older and in those who had a body weight of less than 60 kg. Prasugrel therapy turned on presentation. STEMI patients were given prasugrel as soon as possible after randomization. In those without STEMI, the loading dose was delayed until knowledge of the coronary anatomy. Prasugrel loading was given before crossing the lesion. In patients with a coronary angiography–confirmed acute coronary syndrome who were not considered to be candidates for PCI but who were considered to be candidates for conservative therapy, dual antiplatelet therapy (aspirin and the randomly assigned trial medication) was recommended. About 83% of patients received PCI, 2% CABG and 13-14% were managed conservatively. Clinical follow-up was scheduled at 30 days, 6 and 12 months.Endpoints The primary end point was a composite of death, MI, or stroke at 1 year after randomization. Secondary end points included the safety end point, which was the incidence of bleeding at 1 year (type 3, 4, or 5 on the Bleeding Academic Research Consortium [BARC] scale, which ranges from 0 to 5, with higher values indicating more severe bleeding), the incidence of the individual components of the primary end point at 1 year, and the incidence of definite or probable stent thrombosis at 1 year.The sample-size calculation assumed a primary endpoint would occur in 10% in the ticagrelor group vs 12.9% in the prasugrel group. This led to an estimate of 1900 patients in each group and 80% power to detect a relative risk reduction of 22% in the ticagrelor group. All analyses, including the analysis of the primary end point, were performed according to the intention-to-treat principle Only the safety end point was analyzed in a modified intention-to-treat population, which included all patients who received at least one dose of the randomly assigned trial drug and were assessed for bleeding events up to 7 days after discontinuation of the trial drug.Results At discharge, 81% of patients in both groups received the randomly assigned trial drug. Slightly more patients in the ticagrelor group stopped taking the study drug by one year (15.2 vs 12.5%). One-year follow-up was complete in all but 90 patients (41 patients in the ticagrelor group and 49 patients in the prasugrel group).A primary end-point event (death, MI, stroke) occurred in 184 of 2012 patients (9.1%) in the ticagrelor group and 137 of 2006 patients (6.8%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P=0.006). The composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 161 of 2012 patients (8.1%) in the ticagrelor group and 124 of 2006 patients (6.3%) in the prasugrel group (hazard ratio, 1.32; 95% CI, 1.04 to 1.66).The rates of death, stroke and stent thrombosis did not statistically differ in the two groups. But the risk of MI was 63% higher in the ticagrelor group (4.8% vs 3.0%; HR 1.63; 95% CI, 1.18 to 2.25).Major bleeding was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).No heterogenous treatment effects were obvious from the subgroup analyses. Discussion For patients with acute coronary syndrome who were considered for intervention, prasugrel was superior to ticagrelor for the reduction of the primary endpoint. The effect size was large (ticagrelor 36% worse compared to prasugrel), and this was statistically robust. The reduction was obtained without an increase in bleeding. The trialists noted that this was not simply a comparison of drugs, but a comparison of treatment strategies. Authors had assumed that pre-treatment of ticagrelor would be superior. But this trial showed that a prasugrel-based strategy with deferred loading (after knowing the coronary anatomy) was superior. The primary endpoint finding was bolstered by the composite of cardiovascular death, MI and stroke also being 32% higher in the ticagrelor arm. This was an investigator-initiated non-industry funded study with an event rate in the ticagrelor arm similar to expected findings. We find this compelling evidence for the superiority of prasugrel in this patient population. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.13.523973v1?rss=1 Authors: Steiner, C. A., Koch, S. D., Evanoff, T., Welch, N., Kostelecky, R., Callahan, R., Murphy, E. M., Hall, C. H., Lu, S., Weiser-Evans, M. C., Cartwright, I. M., Colgan, S. P. Abstract: Background & Aims: Crohns disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis. This is in part due to lack of high-fidelity biomimetic models to enhance understanding and drug development. There is a need to develop in vivo models of inflammatory bowel disease-related intestinal fibrosis. We sought to determine if the TNF{Delta}ARE mouse, a model of ileal inflammation, may also develop intestinal fibrosis. Methods: Several clinically relevant outcomes were studied including features of structural fibrosis, histological fibrosis, and gene expression. These include the use of a luminal casting technique we developed, traditional histological outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNF{Delta}ARE mice as well as in cohorts of numerous ages. Results: At ages of 24+ weeks, TNF{Delta}ARE mice develop structural, histological, and genetic changes of ileal fibrosis. Genetic expression profiles have changes as early as six weeks, followed by histological changes occurring as early as 14-15 weeks, and overt structural fibrosis delayed until after 24 weeks. Discussion: The TNF{Delta}ARE mouse is a viable and highly tractable model of intestinal fibrosis. This model and the techniques employed can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trialJenny Downs, Jenny Rodger, Chen Li , Xuesong Tan, Nan Hu, Kingsley Wong , Nicholas de Klerk , Helen LeonardAffiliations expandPMID: 29321033PMCID: PMC5764021DOI: 10.1186/s13023-017-0752-8Free PMC articleAbstractBackground: Rett syndrome is caused by a pathogenic mutation in the MECP2 gene with major consequences for motor and cognitive development. One of the effects of impaired MECP2 function is reduced production of Brain Derived Neurotrophic Factor (BDNF), a protein required for normal neuronal development. When housed in an enriched environment, MECP2 null mice improved motor abilities and increased levels of BDNF in the brain. We investigated the effects of environmental enrichment on gross motor skills and blood BDNF levels in girls with Rett syndrome.Methods: A genetically variable group of 12 girls with a MECP2 mutation and younger than 6 years participated in a modified individually randomised stepped wedge design study. Assessments were conducted on five occasions, two during the baseline period and three during the intervention period. Gross motor function was assessed using the Rett Syndrome Gross Motor Scale (maximum score of 45) on five occasions, two during the baseline period and three during the intervention period. Blood levels of BDNF were measured at the two baseline assessments and at the end of the intervention period. The intervention comprised motor learning and exercise supplemented with social, cognitive and other sensory experiences over a six-month period.Results: At the first assessment, the mean (SD) age of the children was 3 years (1 year 1 month) years ranging from 1 year 6 months to 5 years 2 months. Also at baseline, mean (SD) gross motor scores and blood BDNF levels were 22.7/45 (9.6) and 165.0 (28.8) ng/ml respectively. Adjusting for covariates, the enriched environment was associated with improved gross motor skills (coefficient 8.2, 95%CI 5.1, 11.2) and a 321.4 ng/ml (95%CI 272.0, 370.8) increase in blood BDNF levels after 6 months of treatment. Growth, sleep quality and mood were unaffected.Conclusions: Behavioural interventions such as environmental enrichment can reduce the functional deficit in Rett syndrome, contributing to the evidence-base for management and further understanding of epigenetic mechanisms. Environmental enrichment will be an important adjunct in the evaluation of new drug therapies that use BDNF pathways because of implications for the strengthening of synapses and improved functioning.Trial registration: ACTRN12615001286538 .Keywords: BDNF; Environmental enrichment; Neurodevelopmental disorder; Neuroplasticity; Rett syndrome.

Changes in walking ability, intellectual disability, and epilepsy in adults with cerebral palsy over 50 years: a population-based follow-up studyUlrica Jonsson, Meta Nyström Eek, Katharina Stibrant Sunnerhagen, Kate HimmelmannPMID: 33772773DOI: 10.1111/dmcn.14871AbstractAim: To determine if walking ability and presence of intellectual disability and epilepsy change from childhood to 50 years of age in individuals with cerebral palsy (CP), and if such changes are related to age, sex, or CP subtype.Method: This was a population-based follow-up study of 142 adults born from 1959 to 1978 (82 males, 60 females; mean age 48y 4mo, range 37-58y; 44% unilateral, 35% bilateral, 17% dyskinetic, and 4% ataxic CP) listed in the CP register of western Sweden. We compared childhood data with a follow-up assessment in 2016.Results: At follow-up, walking ability had changed significantly (p

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.220350v1?rss=1 Authors: Bass, J. S., Tuo, A., Ton, L., Jankovic, M., Kapadia, P. P., Schirmer, C., Krishnan, V. Abstract: Objective: Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. Methods: Using instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. Results: At 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Interpretation: Through automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring. Copy rights belong to original authors. Visit the link for more info

Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.

Background: Linear growth is the best clinical parameter for monitoring metabolic control in classical congenital adrenal hyperplasia (CAH). Objective: To analyze growth patterns in children with CAH diagnosed by newborn screening and treated with relatively low doses of hydrocortisone during the first year of life. Patients and Methods: 51 patients (27 females) were diagnosed with classical CAH by newborn screening. All patients were treated with relatively low doses of hydrocortisone (9-15 mg/m(2) body surface area). 47 patients were additionally treated with fludrocortisone. Results: At birth, height SDS (H-SDS) was 1.1 +/- 1 in girls and 0.9 +/- 1.5 in boys. After 3 months, H-SDS decreased to 0.4 +/- 0.9 in girls and to 0.1 +/- 1.3 in boys. Over the 3-year period, H-SDS further decreased to -0.4 +/- 1.8 in girls and to -0.8 +/- 1 in boys and approached the genetic height potential (target H-SDS of girls -0.5 +/- 0.3 and target H-SDS of boys -0.9 +/- 0.7). During the first 9 months of age, growth velocity was slightly decreased in girls (18.2 +/- 1.9 cm) and boys (17.3 +/- 1.6 cm) when compared to a healthy reference population (girls 19.0 +/- 3.9 cm and boys 18.7 +/- 4.7 cm). At the age of 3 years, bone age was appropriate for chronological age in both girls (2.7 +/- 0.5 years) and boys (2.9 +/- 0.5 years). Conclusion: Birth length is above average in children with classical CAH, which might be the result of untreated hyperandrogenism in utero. With relatively low doses of hydrocortisone treatment, growth velocity decreases slightly during the first 9 months and H-SDS then approaches the genetic height potential. Copyright (C) 2010 S. Karger AG, Basel

Background: trans unsaturated fatty acids are thought to interfere with essential fatty acid metabolism. To extend our knowledge of this phenomenon, we investigated the relationship between trans isomeric and long-chain polyunsaturated fatty acids (LCPUFA) in mothers during pregnancy and in their infants at birth. Methods: Fatty acid composition of erythrocyte phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was determined in Spanish (n = 120), German (n = 78) and Hungarian (n = 43) women at the 20th and 30th week of gestation, at delivery and in their newborns. Results: At the 20th week of gestation, the sum of trans fatty acids in PE was significantly (p < 0.01) lower in Hungarian {[}0.73 (0.51), % wt/wt, median (IQR)] than in Spanish {[}1.42 (1.36)] and German {[}1.30 (1.21)] women. Docosahexaenoic acid (DHA) values in PE were significantly (p < 0.01) higher in Hungarian {[}5.65 (2.09)] than in Spanish {[}4.37 (2.60)] or German {[}4.39 (3.3.2)] women. The sum of trans fatty acids significantly inversely correlated to DHA in PCs in Spanish (r = -0.37, p < 0.001), German (n = -0.77, p < 0.001) and Hungarian (r = -0.35, p < 0.05) women, and in PEs in Spanish (r = -0.67, p < 0.001) and German (r = -0.71, p < 0.001), but not in Hungarian (r = -0.02) women. Significant inverse correlations were seen between trans fatty acids and DHA in PEs at the 30th week of gestation (n = 241, r = -0.52, p < 0.001), at delivery (n = 241, r = -0.40, p < 0.001) and in cord lipids (n = 218, r = -0.28, p < 0.001). Conclusion: Because humans cannot synthesize trans isomeric fatty acids, the data obtained in the present study support the concept that high maternal trans isomeric fatty acid intake may interfere with the availability of LCPUFA both for the mother and the fetus. Copyright (C) 2011 S. Karger AG, Basel

Background: Conventional external beam radiotherapy is a standard procedure for treatment of spinal metastases. In case of progression spinal cord tolerance limits further radiotherapy in pre-irradiated areas. Spinal stereotactic radiotherapy is a non-invasive option to re-treat pre-irradiated patients. Nevertheless, spinal radiosurgery results in relevant dose deposition within the myelon with potential toxicity. Aim of the study was to retrospectively analyse the efficacy and feasibility for salvage radiosurgery of spinal metastases. Methods: During a period of 4 years (2005-2009) 70 lesions in 54 patients were treated in 60 radiosurgery sessions and retrospectively analysed. Clinical (pain, sensory and motor deficit) and radiological (CT/MRI) follow-up data were collected prospectively after radiosurgery. Pain - as main symptom - was classified by the Visual Analogue Scale (VAS) score. Every patient received single session radiosurgery after having been treated first-line with conventionally fractionated radiotherapy. Kaplan-Meier method and life tables were used to analyse freedom from local failure and overall survival. Results: At a median follow-up of 14.5 months the actuarial rates of freedom from local failure at 6/12/18 months were 93%, 88% and 85%, respectively. The median radiosurgery dose was 1 x 18 Gy (range 10-28 Gy) to the median 70% isodose. The VAS score of patients with pain (median 6) dropped significantly (median 4, p = 0.002). In 6 out of 7 patients worse sensory or motor deficit after SRS was caused by local or distant failures (diagnosed by CT/MRI). One patient with metastatic renal cell carcinoma developed a progressive complete paraparesis one year after the last treatment at lumbar level L3. Due to multiple surgery and radiosurgery treatments at the lumbar region and further local progression, the exact reason remained unclear. Apart from that, no CTC grade III or higher toxicity has been observed. Conclusions: By applying spinal radiosurgery relevant radiation doses can be limited to small parts of the myelon. This prevents myelopathic side effects and makes it an effective and safe treatment option for well-suited patients. Especially for previously irradiated patients with local failure or pain salvage SRS represents a valuable treatment option with high local control rates, low toxicity and significant pain reduction.

Background: Laser acceleration of protons and heavy ions may in the future be used in radiation therapy. Laser-driven particle beams are pulsed and ultra high dose rates of >10(9) Gy s(-1) may be achieved. Here we compare the radiobiological effects of pulsed and continuous proton beams. Methods: The ion microbeam SNAKE at the Munich tandem accelerator was used to directly compare a pulsed and a continuous 20 MeV proton beam, which delivered a dose of 3 Gy to a HeLa cell monolayer within < 1 ns or 100 ms, respectively. Investigated endpoints were G2 phase cell cycle arrest, apoptosis, and colony formation. Results: At 10 h after pulsed irradiation, the fraction of G2 cells was significantly lower than after irradiation with the continuous beam, while all other endpoints including colony formation were not significantly different. We determined the relative biological effectiveness (RBE) for pulsed and continuous proton beams relative to x-irradiation as 0.91 +/- 0.26 and 0.86 +/- 0.33 (mean and SD), respectively. Conclusions: At the dose rates investigated here, which are expected to correspond to those in radiation therapy using laser-driven particles, the RBE of the pulsed and the (conventional) continuous irradiation mode do not differ significantly.

Background: Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIVinfected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells. Methods: By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed. Results: At a concentration of 9 mu g/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 mu g/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 mu g/ml), but did not have additional detrimental effects on non-malignant bone marrow cells. Conclusions: The ability of nelfinavir to induce apoptosis in leukemia cells as a single agent in a mitochondria-independent manner might suggest it could be used as a second or third line of treatment for leukemia patients for whom standard mitochondria-directed treatment strategies have failed. Combination treatment with nelfinavir and sorafenib might further enhance the efficacy of nelfinavir even on chemo-resistant leukemia cells.

Purpose: The goal of this treatment trial was to investigate the efficacy of an inpatient group therapy program specifically designed for patients suffering from Obsessive Compulsive Disorder (OCD, ICD 10, F 42). Methods: In the experimental group (EG; n = 14) the specific group therapy was carried out in addition to individual cognitive-behavioral therapy, the control group (KG; n = 16) received non-specific group therapy in mixed patient-groups in addition to individual therapy. 7 patients (EG = 3, KG = 4) received also Selective Serotonin re-uptake inhibitors (SSRIs). Y-BOCS, BDI, and STAI-X1 were performed pre- and post-treatment. Furthermore therapists' ratings and self ratings were taken. Results: At post-treatment both groups showed significant improvement of the symptomatology. For the EG the Y-BOCS mean was reduced from 23.64 to 11.35, for the KG from 23.81 to 12.81. The group comparison showed no significant differences (alpha = 0.05) in clinical measurements, therapists' and self ratings. However, there were significantly more responders (improvement >50%, Y-BOCS) in the EG and treatment duration was shorter by 15 days. Conclusions: Clinical outcome in the EG was not superior. However, the specific group therapy for OCD contributes to an economic and effective treatment.

Background/Aim: Previous studies in vitro and in animals in vivo found that alpha-linolenic acid (C18:3 omega 3) may enhance oxidative damage of essential amino acids. We investigated whether the addition of the long-chain polyunsaturated fatty acids (LCPUFA) arachidonate (C20:4 omega-6; AA) and docosahexaenoate (C22:6-omega 3; DHA) in the form of egg phospholipids to infant formula affects plasma amino acid concentrations and indices of protein metabolism in term infants. Methods: In a double-blind, randomized clinical trial, healthy infants were fed from day 5 of life formula with or without preformed LCPUFA (n = 10 and 12, respectively). At the age of 5 days and 1, 2, 3 and 4 months, blood samples were obtained and analyzed for plasma amino acids by high-performance liquid chromatography and for plasma phospholipid fatty acid composition by gas chromatography. Results: At the age of 3 months, plasma threonine concentrations were significantly lower in infants receiving dietary LCPUFA than in controls (124 +/- 16 vs. 216 +/- 28 mu mol/l, p < 0.05). Values of other plasma essential amino acids, total protein, albumin, creatinine and urea nitrogen did not differ between the two feeding groups throughout the study. At the age of 5 days, plasma phospholipid AA and DHA concentrations were inversely correlated with histidine concentrations (AA: r = -0.60, p = 0.01; DHA: r = -0.53, p < 0.05). At the age of 3 months, DHA concentrations were inversely related to plasma histidine, methionine and threonine concentrations (r = -0.66, -0.62, and -0.64, respectively, p < 0.05). Conclusions: The dietary LCPUFA supplementation of infant formula used in this study has no adverse effects on infant plasma amino acid concentrations and indicators of protein metabolism. Nonetheless, the apparent interaction of LCPUFA with some amino acids in formula-fed infants warrants further investigation.