Diffusivity interfaces in lattice Monte Carlo simulations: Modeling inhomogeneous delivery and release systems.

Lattice Monte Carlo (LMC) simulations are widely used to investigate diffusion-controlled problems such as drug-release systems. The presence of an inhomogeneous diffusivity environment raises subtle questions about the interpretation of stochastic dynamics in the overdamped limit, an issue sometimes referred to as the "Ito-Stratonovich-isothermal dilemma." We propose a LMC formalism that includes the different stochastic interpretations in order to model the diffusion of particles in a space-dependent diffusivity landscape. Using as an example a simple inhomogeneous one-dimensional system with a diffusivity interface and different boundary conditions, we demonstrate that we can properly reproduce the steady state and dynamic properties of these systems and that these properties do depend on the choice of calculus. In particular, we argue that the version of the LMC algorithm that uses Ito calculus, which is commonly used to model drug delivery systems, should be replaced by the isothermal version for most applications. Our LMC methodology provides an efficient alternative to Langevin simulations for a wide class of space-dependent diffusion problems.

Oncolytic adenovirus ORCA-010 increases the type 1 T cell stimulatory capacity of melanoma-conditioned dendritic cells.

Immune checkpoint blockade has resulted in durable responses in patients with metastatic melanoma, but only in a fraction of treated patients. For immune checkpoint inhibitors (ICI) to be effective, sufficient infiltration with tumor-reactive T cells is essential. Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and so induce an immunogenic form of cell death, providing at once a source of tumor-associated (neo)antigens and of danger signals that together induce effective T cell immunity and tumor infiltration. Melanoma-associated suppression of dendritic cell (DC) differentiation effectively hampers OV- or immune checkpoint inhibitor (ICI)-induced anti-tumor immunity, due to a consequent inability to prime and attract anti-tumor effector T cells. Here, we set out to study the effect of ORCA-010, a clinical stage oncolytic adenovirus, on DC differentiation and functionality in the context of human melanoma. In melanoma and monocyte co-cultures, employing a panel of five melanoma cell lines with varying origins and oncogenic mutation status, we observed clear suppression of DC development with apparent skewing of monocyte differentiation to a more M2-macrophage-like state. We established the ability of ORCA-010 to productively infect and lyse the melanoma cells. Moreover, although ORCA-010 was unable to restore DC differentiation, it induced activation and an increased co-stimulatory capacity of monocyte-derived antigen-presenting cells. Their subsequent ability to prime effector T cells with a type I cytokine profile was significantly increased in an allogeneic mixed leukocyte reaction. Our findings suggest that ORCA-010 is a valuable immunotherapeutic agent for melanoma.

Genetic determinants of activity and antigen levels of contact system factors.

Essentials Genetic variation may provide valuable insight into the role of the contact system in thrombosis. Explored associations of genetic variants with activity, antigen, and disease in RATIO study. Two novel loci were identified: KLKB1 rs4253243 for prekallikrein; KNG1 rs5029980 for HMWK levels. Contact system variants and haplotypes were not associated with myocardial infarction or stroke. SUMMARY: Background The complex, interdependent contact activation system has been implicated in thrombotic disease, although few genetic determinants of levels of proteins from this system are known. Objectives Our primary aim was to study the influence of common F11, F12, KLKB1, and KNG1 variants on factor (F) XI activity and FXI, FXII, prekallikrein (PK) and high-molecular-weight kininogen (HMWK) antigen levels, as well as the risk of myocardial infarction and ischemic stroke. Patients/methods We analyzed samples from all 630 healthy participants, 182 ischemic stroke patients and 216 myocardial infarction patients in the RATIO case-control study of women aged < 50 years. Forty-three tagging single nucleotide variants (SNVs) were genotyped to represent common genetic variation in the contact system genes. Antigen and activity levels were measured with sandwich-ELISA-based and one-stage clotting assays. We performed single variant, age-adjusted, linear regression analyses per trait and disease phenotype, assuming additive inheritance and determined conditionally independent associations. Haplotypes based on the lead SNV and all conditionally independent SNVs were tested for association with traits and disease. Results We identified two novel associations of KLKB1 SNV rs4253243 with PK antigen (ßconditional = -12.38; 95% CI, -20.07 to -4.69) and KNG1 SNV rs5029980 with HMWK antigen (ßconditional = 5.86; 95% CI, 2.40-9.32) and replicated previously reported associations in a single study. Further analyses probed whether the observed associations were indicative of linkage, pleiotropic effects or mediation. No individual SNVs or haplotypes were associated with the disease outcomes. Conclusion This study adds to current knowledge of how genetic variation influences contact system protein levels and clarifies interdependencies.

Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.

Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.

Male-specific risk of first and recurrent venous thrombosis: a phylogenetic analysis of the Y chromosome.

Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E-carriers may have an increased risk of recurrent VT, but a larger study is needed. SUMMARY: Background The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case-control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3-86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6-46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk.

[Substance use and criminality: a review]. / Middelengebruik en criminaliteit: een overzicht.

BACKGROUND: Substance use regularly co-occurs with many types of criminality, including violent behaviour. AIM: To review the relationships between substance abuse and criminality, which can involve violent behaviour. METHOD: We searched the literature for meta-analyses, reviews and empirical articles about relationships between the problematic use of and addiction to psychoactive substances on the one hand and antisocial and aggressive behaviour and recidivism on the other hand. RESULTS: In the case of both men and women there are significant relationships between substance abuse and criminal behavior. The majority of substance users, however, are not criminals and most of the offences they commit can be termed 'acquisitive offences'. The relationship between alcohol and violence is stronger than the relationship between substance abuse and violence. Furthermore, it is only in cocaine users that we find indications that psychopharmacological effects stimulate violent behaviour. A number of factors, particularly interactions, determine whether substance abusers are criminal and are violent. Violent behaviour can result from interactions between the severity of illness caused by substance abuse, individual psychological, social and neurobiological characteristics, situational factors and expectancies regarding the psychopharmacological effects of a particular substance. CONCLUSION: Substance abuse, particularly the combination of alcohol and drugs, is a predictor of criminality and criminal recidivism.

Bilateral round ligament varicosities mimicking inguinal hernia during pregnancy.

Round ligament varicosities during pregnancy have not been reported extensively. The swelling mimics an inguinal hernia and should be considered in the differential diagnosis of a groin swelling during pregnancy. We report a case of a pregnant woman with bilateral round ligament varicosities. At 22 weeks of pregnancy she was operated on based on the clinical suspicion of a painful inguinal hernia on the right side. Surgical exploration revealed varicosities of the round ligament, and resection was performed. Four weeks later the same diagnosis was made by duplex sonography of a painful swelling in the left groin. Increased pain necessitated surgical exploration and resection of the varicosities on the left side. The postoperative course on both sides was uneventful and without pain during the rest of her pregnancy, during labor or post partum.

First Dutch national guidelines--pharmacological care for detained opioid addicts.

Heterogenic care of addicted detainees in the various prisons in The Netherlands triggered the National Agency of Correctional Institutions of the Ministry of Justice, to order the Dutch Institute for Health Care Improvement (CBO) to formulate the first national guideline titled 'Pharmacological care for detained addicts'. This article presents the content of this guideline, which mainly focuses on opioid-dependent addicts. In The Netherlands, approximately 50% of the detainees are problematic substance abusers, while again half of this group suffers from psychiatric co-morbidity. In addition, somatic co-morbidity, especially infectious diseases, is also common. Due to the moderate outcome seen with voluntary drug counselling regimes in prison, there is a policy shift to extent utilization of legally enforced approaches. Continuity of care is of great importance. In case of opioid addicts this, in general, means continuation of methadone maintenance treatment. Aftercare immediately after detention and optimalization of medical information transfer is crucial. This guideline aims to realize optimal and uniform management of addiction disorders in the Dutch prison system.

[Endometrial and ovarian tumours and their association with obesity]. / Tumoren van endometrium en ovarium en de samenhang met obesitas.

A 53-year-old woman was wheelchair-dependent and unable to work due to an extreme increase in abdominal circumference. Closer investigation revealed an ovarian tumour. A mucinous cystadenoma of the ovary weighing more than 20 kg was removed with laparotomy. A 63-year-old woman presented with postmenopausal haemorrhage. Morbid obesity and agoraphobia had prevented her from visiting a doctor earlier. She was eventually diagnosed with stage 1C grade III endometrial carcinoma, which was treated with surgery and vaginal brachytherapy. The incidence of gynaecological tumours is increased in patients with a high BMI. This association is stronger for endometrial carcinoma than for ovarian carcinoma. Obesity has a favourable influence on the histological grade of endometrial carcinoma, and is associated with lower-stage ovarian cancer. Surgery-related complications are more common in obese patients. Determining the optimal dose of adjuvant therapy is also problematic in obese patients.

Metabolically assessed muscle fibre recruitment in brief isometric contractions at different intensities.

This study investigated the recruitment of type I, IIA and IIAX fibres after seven isometric contractions at 40, 70 and 100% maximal voluntary knee extension torque (MVC, 1 s on/1 s off). Biopsies of the vastus lateralis muscle were collected from seven subjects at rest and immediately post-exercise. Fibre fragments were dissected from the freeze-dried samples and characterized as type I, IIA and IIAX using mATPase staining. Phosphocreatine (PCr) and creatine (Cr) content were measured in the remaining part of characterized fibres. A decline in the ratio of PCr to Cr (PCr/Cr) was used as an indication of activation. The mean peak torques were, respectively, 39 (2), 72 (2) and 87 (6)% MVC. Cumulative distributions of type I and IIA fibres were significantly shifted to lower PCr/Cr ratios at all intensities (Kolmogorov-Smirnov test, P<0.05). The cumulative distribution of type IIAX fibres showed a significant leftward shift only at 87% MVC ( P<0.05). A hierarchical order of fibre activation with increasing intensity of exercise was found, with some indication of rate coding for type I and IIA fibres. Evidence for activation of type IIAX fibres was only found at 87% MVC.

Changes in PCr/Cr ratio in single characterized muscle fibre fragments after only a few maximal voluntary contractions in humans.

AIM: This methodological study investigated the number of brief maximal voluntary isometric contractions (MVC) needed to show evidence of fibre activation, as indicated by changes in the phosphocreatine to creatine (PCr/Cr) ratio. METHODS: Subjects performed series of four, seven and/or 10 MVC (1 s on, 1 s off) of the m. quadriceps (60 degrees -flexion angle). Biopsy samples of the m. vastus lateralis were taken at rest and immediately post-exercise. Single muscle fibres were dissected from the freeze-dried samples and classified as types I, IIA or IIAX, using mATPase stainings. Fragments of characterized fibres were analysed for PCr and Cr content. Analyses of variance were performed to investigate changes in PCr/Cr per fibre group over time, followed by Bonferroni post-hoc test (P < 0.01). The fifth percentile of resting values of each fibre group was determined. RESULTS: Mean PCr/Cr ratio after four, seven and 10 MVCs were significantly lower for all fibre groups (P < 0.01). The mean decreases were 44, 64 and 76%, respectively. However, only after seven and 10 contractions PCr/Cr ratios of all, but three type I and two type IIAX fibres, individual fibres were below the fifth percentile. CONCLUSION: In very short duration exercise, involving seven brief maximal voluntary contractions, changes in the PCr/Cr ratio indicated activation of different characterized muscle fibre fragments. The results suggest that this approach may be useful for investigating the pattern of fibre type activation in exercise of very short duration.

[Unavoidable surgical intervention in two women with severe actinomycosis during IUD use]. / Onvermijdelijke chirurgische interventie bij twee IUD-draagsters met ernstige actinomycose.

Extensive abdominal infections with Actinomyces were diagnosed in two women aged 35 and 33 years respectively, who suffered from the nonspecific symptoms fever and abdominal pain. These infections occur more often in women with an intrauterine device. Development of an abdominal mass with ureter or bowel obstruction may cause hydronephrosis and mechanical ileus. The patients underwent a laparotomy and a double-J catheter was inserted, which could be removed later on (temporary stoma). Treatment included high-dose penicillin i.v. followed by oral amoxicillin. Both patients recovered. It may be difficult to establish this diagnosis: the first patient was diagnosed by histopathological examination, in the second Actinomyces had been found in a routine cervical smear a few years earlier.

[Diagnostic image (165). A woman with an inguinal mass. Lymphangitis carcinomatosis spread to the skin by metastases of an ovarian carcinoma]. / Diagnose in beeld (165). Een vrouw met een inguïnale zwelling. Lymphangitis carcinomatosa met doorgroei in de huid door metastasering van een ovariumcarcinoom.

In a 57-year-old woman ovarian cancer spread lymphogenically to the groin and suprapubic skin.

Event-related brain potentials evoked by verbs and nouns in a primed lexical decision task.

We investigated whether verbs and nouns evoke comparable behavioral and N400 effects in a primed lexical decision task. Twenty-nine students were tested, 13 in a pilot study in which only response times and error rates were collected and 16 in a study in which ERPs were recorded from 124 scalp electrodes. Stimuli were noun-noun and verb-verb pairs with the targets bearing either a strong, a moderate, or no semantic association to the prime or being a pseudoword. Behavioral data revealed comparable priming effects for both word categories. These proved to be independent from the SOA (250 and 800 ms) and they followed the well-known pattern of decreasing response times and error rates with increasing relatedness between target and prime. ERPs revealed pronounced N400 effects for both word categories with a larger amplitude for noun than for verb pairs. A systematic analysis of topographic differences between noun- and verb-evoked ERPs and N400 effects, respectively, gave no convincing support to the hypothesis that the two word categories activate distinct neuronal networks.

Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep.

OBJECTIVE: To assess the clinical utility of overshoot fetal heart rate (FHR) decelerations by examining their occurrence after umbilical cord occlusions of varying frequency and length in near-term fetal sheep. METHODS: Fetuses were allocated to the following three groups: 1-minute umbilical cord occlusion repeated every 5 minutes (1:5 group, n = 8) or every 2.5 minutes (1:2.5 group, n = 8) or 2-minute occlusions repeated every 5 minutes (2:5 group, n = 4). Occlusions were continued for 4 hours or until fetal mean arterial pressure decreased below 20 mmHg during two successive occlusions. RESULTS: In the 1:5 group, fetuses tolerated 4 hours of occlusion without hypotension or clinically significant acidosis and overshoot never occurred. In the 2:5 group, fetuses rapidly became hypotensive and acidotic, and occlusions were terminated at 116.3 +/- 22.9 min (mean +/- standard deviation). Overshoot was seen after every occlusion, starting with the first occlusion. In the 1:2.5 group, fetuses became progressively acidotic and hypotensive and occlusions were stopped at 183.1 +/- 42.8 min. Overshoot occurred after 91.6 +/- 42.5 minutes, at a pH of 7.17 +/- 0.06, base deficit 9.3 +/- 4.5 mmol/L. After the appearance of overshoot there was a more rapid decrease in fetal mean arterial pressure (0.25 [0.21, 0.35, 25-75th percentile] mmHg/minute versus 0.11 [0.03, 0.15] mmHg/minute before overshoot appeared, P <.01). CONCLUSION: These data suggest that overshoot is related to longer (2-minute) occlusions or to developing fetal acidosis and hypotension during 1-minute occlusions. This pattern could have clinical utility, as 1-minute contractions are typical of active labor.

Treatment of systemic lupus erythematosus with LJP 394.

OBJECTIVE: LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life. METHODS: This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period. RESULTS: The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups. CONCLUSION: This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.

Individual cortical current density reconstructions of the semantic N400 effect: using a generalized minimum norm model with different constraints (L1 and L2 norm).

Event-related brain potentials were recorded to study whether verbs and nouns activate topographically distinct cortical generators. Fifteen subjects performed a primed lexical decision task with verb/verb and noun/noun pairs. The relatedness between prime and target items was varied in three steps (unrelated, moderately, and strongly related) and the EEG was recorded from 124 scalp electrodes. The topography of cortical sources of the N400 effect was evaluated by standardized differences scores and by cortical current source estimates which were constrained by the individual MRI-determined cortex anatomy. A behavioral priming effect and a substantial N400 effect was found for both word categories. However, the topography of the grand average N400 effect of verbs and nouns did not differ, neither for raw nor for standardized amplitudes. Cortical current source estimates of the N400 effect revealed a very broad and scattered distribution of active locations with pronounced interindividual differences. Cortical current source estimates obtained with the L1-norm and L2-norm model, respectively, differed in the distribution of sources over the cortex but converged on the same "hot spots." The data give no indication that the N400 effect is generated by word category-specific networks which have a different topography. The marked individual differences are discussed with respect to the involved processes and the current source estimation procedures.