Valproate Induces in Vitro Accumulation of Long-Chain Fatty Acylcarnitines

To elucidate the interference mechanisms of valproate (VPA) with mitochondrial fatty acid β-oxidation (FAO), the profile of acylcarnitine formation was studied in vitro. Human fibroblasts were incubated with 0.2 mmol/L [U-¹³C]palmitate, 0.4 mmol/L -carnitine, ± VPA (2 mmol/L) (96 h at 37°C). Acylcarnitines (AC) were analyzed by GC-CI-MS. VPA induced an impaired production of acetylcarnitine (C2) and an increase on long-chain AC (C10 to C16) both in control and in FAO-deficient cell lines (VLCAD, LCHAD, MTP).     

Disorganized attachment in infancy: a review of the phenomenon and its implications for clinicians and policy-makers

Disorganized/Disoriented (D) attachment has seen widespread interest from policy makers, practitioners, and clinicians in recent years. However, some of this interest seems to have been based on some false assumptions that (1) attachment measures can be used as definitive assessments of the individual in forensic/child protection settings and that disorganized attachment (2) reliably indicates child maltreatment, (3) is a strong predictor of pathology, and (4) represents a fixed or static “trait” of the child, impervious to development or help. This paper summarizes the evidence showing that these four assumptions are false and misleading. The paper reviews what is known about disorganized infant attachment and clarifies the implications of the classification for clinical and welfare practice with children. In particular, the difference between disorganized attachment and attachment disorder is examined, and a strong case is made for the value of attachment theory for supportive work with families and for the development and evaluation of evidence-based caregiving interventions.     

Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy: A Feasible and Effective Option for Colorectal Cancer Patients After Emergency Surgery in the Presence of Peritoneal Carcinomatosis

Background

When peritoneal carcinomatosis (PC) is diagnosed during emergency surgery for colorectal cancer (CRC), further treatment with curative intent may seem futile given the known poor prognosis of both PC and emergency surgery. The aim of the current study was to investigate the feasibility and effectiveness of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for CRC patients who previously underwent emergency surgery in the presence of PC.

Methods

All patients with synchronous PC of CRC referred to two tertiary centers between April 2005 and November 2013 were included in this study. Operative, postoperative and survival details were compared between patients presenting in an emergency or elective setting.

Results

In total, 149 patients with synchronous PC underwent CRS and HIPEC. Amongst these patients, 36 (24.2 %) initially presented with acute symptoms requiring emergency surgery. Acute presentation did not result in a longer interval between the initial operation and HIPEC (2.2 vs. 2.1 months; P = 0.09). When comparing operative outcomes, no significant differences were found in blood loss (P = 0.47), operation time (P = 0.39), or completeness of cytoreduction (P = 0.97). In addition, complication rates, degree and types of complication did not differ between the groups. Median survival was 36.1 months for emergency presentation compared with 32.1 in the elective group (P = 0.73).

Conclusion

CRS + HIPEC may be performed safely in patients with PC of colorectal origin presenting with acute symptoms requiring emergency surgery. More importantly, the 5-year survival rate in these patients was equal to elective cases. This should be regarded as promising and therefore considered for these patients.     

A cornerstone of heart failure treatment is not effective in experimental right ventricular failure

Background

Right ventricular (RV) failure due to increased pressure load causes significant morbidity and mortality in patients with congenital heart diseases and pulmonary arterial hypertension. It is unknown whether renin–angiotensin–aldosterone-system (RAAS) inhibition (the cornerstone of left ventricular failure treatment) is effective in RV failure. We investigated the effects of combination treatment of aldosterone-blocker eplerenone + angiotensin II receptor blocker losartan (Ep/Lo) on RV remodeling and function in a model of RV failure due to increased pressure load.

Methods and results

Rats (n = 48) were randomized for pulmonary artery banding (PAB) or sham surgery and for losartan (20 mg/kg/d) + eplerenone (100 mg/kg/d) treatment (Ep/Lo) or vehicle (VEH). RV function was assessed by echocardiography and pressure–volume analysis at 5 and 11 weeks, or at the occurrence of clinical RV failure symptoms necessitating termination.PAB resulted in RV failure in all rats, as defined by reduced cardiac output, RV stroke volume, increased RV end diastolic pressure and liver congestion as well as RV fibrosis, hypertrophy and reduced capillary density. Clinical RV failure necessitated termination in 5/12 PAB–VEH rats. Angiotensin II type 1-receptor expression in the RV was reduced in PAB rats indicating local RAAS activation. Treatment of PAB rats with Ep/Lo significantly lowered arterial pressures, but had no significant effect on RV function, remodeling or survival compared to PAB–VEH rats.

Conclusions

RAAS inhibition does not beneficially affect experimental RV failure due to chronic pressure load. This is of high clinical relevance, because it indicates that the RV response to RAAS inhibition might fundamentally differ from that of the LV.     

FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility

OBJECTIVE: To evaluate the ability of a prediction model to identify the individual starting dose of FSH for ovulation induction using a step-down regimen. DESIGN: Retrospective analysis of clinical data in an academic fertility unit. Fifty-six normogonadotropic anovulatory infertile patients who failed to ovulate or conceive with clomiphene citrate were included. They were treated with exogenous gonadotropins with a flexible starting dose for ovulation induction using a step-down regimen. The clinically applied starting dose of exogenous gonadotropins was compared with the calculated response-dose using a previously published prediction model. RESULTS: Patients were arbitrarily divided into three groups according to the day of the first decrease in gonadotropin dose: (a) early step-down (day 3 or earlier); (b) standard step-down (day 4 or later); (c) no step-down. These groups had average starting doses of 28.5 IU (group a) and 13 IU (group b) above the calculated response-dose, and 43 IU (group c) under the calculated response-dose. A significant correlation between day of first step-down and the difference between clinically applied and calculated response-dose was observed (P<0.0001, F-test for ANOVA). CONCLUSIONS: The patient group with the best step-down profile for ovulation induction exhibited the closest match between the clinically applied and calculated starting dose of gonadotropins. Therefore, this study provides support for the concept that the individual effective FSH starting dose for gonadotropin induction of ovulation in anovulatory infertile patients can be predicted on the basis of initial screening characteristics, such as body mass index, clomiphene resistance or failure, free IGF-I and FSH. This may result in more effective patient treatment protocols, reduced complication rates and health-economic benefits.     

Focal brain matter differences associated with lifetime alcohol intake and visual attention in male but not in female non-alcohol-dependent drinkers

The purpose of this study was to investigate whether current or lifetime alcohol intake is related to focal gray and white matter in healthy non-alcohol-dependent drinkers, and, if so, whether these densities are related to functional brain activity associated with visual attention. Voxel-based morphometric analyses of gray- and white-matter densities, and event-related potentials in response to a visual-attention task were determined in 47 male drinkers (current alcohol intake 20 drinks per week, lifetime alcohol intake 240 kg) and 44 female drinkers (current alcohol intake 15 drinks per week, lifetime alcohol intake 170 kg). All participants had a negative personal and family history of alcohol dependence to reduce possible confounding by genetic factors related to alcohol dependence. In males, mean lifetime alcohol intake was negatively associated with gray-matter density and positively associated with white-matter density in the right frontal gyrus (BA 6) and the right parietal region (BA 40). Right frontal (but not right parietal) gray and white matter in males correlated with the P3 amplitude of the event-related potentials elicited in a visual-attention task. In females, mean lifetime alcohol intake was not associated with gray- or white-matter density. Current alcohol intake was unrelated to gray or white matter in both males and females. In conclusion, lifetime alcohol intake is associated with focal gray-matter decreases and white-matter increases in the right frontal and right parietal brain regions in non-alcohol-dependent males, but not in females. These alcohol-related differences in focal brain matter in males are associated with differences in brain function related to visual attention. As the confounding effects of genetic factors were reduced, the present results may selectively relate to the effects of alcohol intake on focal brain matter.     

CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack

To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy. However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli. Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation. These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing. CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri. Unexpectedly, the BH3-only protein Bid was strongly induced. Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation. Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation. Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells. These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induced.     

Genetic HLA Associations in Complex Regional Pain Syndrome With and Without Dystonia

We previously showed evidence for a genetic association of the human leukocyte antigen (HLA) system and complex regional pain syndrome (CRPS) with dystonia. Involvement of the HLA system suggests that CRPS has a genetic component with perturbed regulation of inflammation and neuroplasticity as possible disease mechanisms. However, it is at present unclear whether the observed association with HLA-B62 and HLA-DQ8 in CRPS patients with dystonia also holds true for patients without dystonia. Therefore, we tested the possible association with HLA-B62 and HLA-DQ8 in a clinically homogeneous group of 131 CRPS patients without dystonia. In addition, we investigated the possible association with other alleles of the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci. We showed an increased prevalence of HLA-DQ8 (molecularly typed as HLA-DQB1*03:02; OR = 1.65 [95% CI 1.12–2.42], P = .014) in CRPS without dystonia, whereas no association was observed for HLA-B62 (molecularly typed as HLA-B*15:01; OR = 1.22 [95% CI .78–1.92], P = .458). Our data suggest that CRPS with and CRPS without dystonia may be genetically different, but overlapping, disease entities because only HLA-DQ8 is associated with both. The findings also indicate that distinct biological pathways may play a role in both CRPS subtypes.PerspectiveThis study is the first to replicate a specific HLA region conferring genetic risk for the development of CRPS. Moreover, associations of HLA-DQ8 with both CRPS with and CRPS without dystonia, and HLA-B62 only with CRPS with dystonia, suggest that these disease entities may be genetically different, but overlapping.     

Treatment strategies in advanced stage follicular lymphoma

Although the introduction of anti-CD20 monoclonal antibodies has improved the outcome of patients with follicular lymphoma, a curative treatment is still not available. Many questions still remain to be answered: when should treatment be initiated? Is there an optimal first line treatment and can this treatment be individualized on the basis of prognostic markers? What is the best treatment strategy for relapsed follicular lymphoma and what is the place of the many novel agents? Should maintenance treatment be given to all patients and how? In the present review we will address these questions.     

Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial

We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+ non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P=.01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P<.001), and progression free survival (PFS24; 52% vs 31% P<.002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24 (HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.