Search

Background: Children of parents with a mental disorder and/or addiction (COPMI) are at increased risk of developing a mental disorder. In spite of preventive interventions that can decrease the risk of problem development, COPMI are not automatically offered help. In 2013, a mandatory COPMI check was implemented in the Netherlands, requiring every mental health care professional to check whether their adult patients have children and to assess these children's safety and needs. Earlier research has shown that a gap between these regulations and the actual integration in clinical practice is not uncommon., Method: In the current study, we evaluated the implementation of the mandatory COPMI check in the Netherlands, using quantitative as well as qualitative data from a large mental healthcare organization in the Netherlands that offers both Child and Adolescent Mental Health and Adult Mental Healthcare., Results: Files from 14,469 patients were analyzed quantitatively and a sample of 150 files was further analyzed in depth. Findings were refined through 4 focus groups with adult mental healthcare professionals. It was found that while there are examples of the tool leading to interventions for COPMI, the tool is often not used, and when used tends to direct the focus away from COPMI needs and organizing help toward the more narrow and problematic focus on safety and reporting to child abuse authorities., Conclusion: The potential of the COPMI check is currently not fully realized. Strategies to improve its effectiveness in clinical practice are needed to improve access to interventions for COPMI., Competing Interests: SE and TA are involved as employees at the mental healthcare facility where the research was conducted. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Everts, van Amelsvoort and Leijdesdorff.)

In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2°) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood-brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long-lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets., Competing Interests: The authors declare no conflict of interest.

Background: Cure rates for children and young adults with osteosarcoma have remained stagnant over the past three decades. Targeting glycoprotein non-metastatic b (GPNMB) with the antibody-drug conjugate glembatumumab vedotin has improved outcomes for patients with melanoma and breast cancer. The potential utility of targeting GPNMB in osteosarcoma was explored., Methods: GPNMB protein expression was evaluated by immunohistochemistry in human osteosarcoma tumor samples and by enzyme-linked immunosorbent assay (ELISA) in osteosarcoma cell lines. mRNA expression was measured by quantitative PCR in primary osteosarcoma samples and cell lines. Surface GPNMB expression was evaluated by flow cytometry and correlated with in vitro and in vivo cytotoxicity of glembatumumab vedotin., Results: Sixty seven human osteosarcoma samples were evaluated by immunohistochemistry, including 12 samples from initial biopsy, 38 samples from definitive surgery, and 17 from the time of disease recurrence. GPNMB was expressed in 92.5% (62/67) of osteosarcoma samples. All primary osteosarcoma samples expressed high levels of GPNMB mRNA. Glembatumumab induced cytotoxic effects in 74% (14/19) of osteosarcoma cell lines, and GPNMB protein levels correlated with glembatumumab in vitro cytotoxicity (r = -0.46, P = 0.04). All osteosarcoma cell lines demonstrated surface GPNMB expression., Conclusions: GPNMB is expressed in osteosarcoma and targeting GPNMB with the antibody-drug conjugate glembatumumab vedotin demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma., (© 2015 Wiley Periodicals, Inc.)

Background: Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures., Methods: In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters., Findings: In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·9×10(-10)). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10(-20)). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes., Interpretation: These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness., Funding: German Research Foundation (Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain), Max Planck Society, Max Planck Förderstiftung, EXTRABRAIN EU-FP7, ERA-NET NEURON., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

During cardiogenesis the epicardium, covering the surface of the myocardial tube, has been ascribed several functions essential for normal heart development of vertebrates from lampreys to mammals. We investigated a novel function of the epicardium in ventricular development in species with partial and complete septation. These species include reptiles, birds and mammals. Adult turtles, lizards and snakes have a complex ventricle with three cava, partially separated by the horizontal and vertical septa. The crocodilians, birds and mammals with origins some 100 million years apart, however, have a left and right ventricle that are completely separated, being a clear example of convergent evolution. In specific embryonic stages these species show similarities in development, prompting us to investigate the mechanisms underlying epicardial involvement. The primitive ventricle of early embryos becomes septated by folding and fusion of the anterior ventricular wall, trapping epicardium in its core. This folding septum develops as the horizontal septum in reptiles and the anterior part of the interventricular septum in the other taxa. The mechanism of folding is confirmed using DiI tattoos of the ventricular surface. Trapping of epicardium-derived cells is studied by transplanting embryonic quail pro-epicardial organ into chicken hosts. The effect of decreased epicardium involvement is studied in knock-out mice, and pro-epicardium ablated chicken, resulting in diminished and even absent septum formation. Proper folding followed by diminished ventricular fusion may explain the deep interventricular cleft observed in elephants. The vertical septum, although indistinct in most reptiles except in crocodilians and pythonidsis apparently homologous to the inlet septum. Eventually the various septal components merge to form the completely septated heart. In our attempt to discover homologies between the various septum components we aim to elucidate the evolution and development of this part of the vertebrate heart as well as understand the etiology of septal defects in human congenital heart malformations.

HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) (14)C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4(+) cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58-77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38-76) half-life; Cmax was 20 fmol/million cells (2-63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1-281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.

Background: Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG)., Methods: Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period., Results: In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87)., Conclusions: Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

We compared the activity estimated by a pedometer and an accelerometer in coronary artery disease patients included in a phase III cardiac rehabilitation programme. Nine patients were divided into two groups and wore the pedometer for four weeks, and then subsequently the accelerometer for four weeks, or vice versa. The recorded daily exercise level (total daily steps and calories burned) was measured for each patient and compared with oxygen uptake and ventilatory threshold measured by ergospirometry at the end of the study. There was a significant correlation between the calories measured by the accelerometer and the ventilatory threshold (i.e. the sub-maximal capacity), r = 0.75 (P = 0.05). There was a significant correlation between the measured steps on the accelerometer and the ventilatory threshold, r = 0.72 (P = 0.07). There were no significant correlations for the pedometer. A questionnaire concerning ease of use of the sensors indicated that the cardiac patients favoured the pedometer.

Background: Many antiretroviral drugs used in HIV care involve complex drug metabolism by CYP3A4 and CYP2D6 enzymes, and drug interactions are problematic clinically. AMD070, a novel entry inhibitor, is an inhibitor of X4-tropic HIV virus. In vitro data suggested that it is a CYP3A4 substrate and may inhibit CYP2D6 and CYP3A4., Methods: Twelve healthy subjects were given a single oral dose of 5 mg of midazolam and 30 mg of dextromethorphan on day 1 and 9, and 200 mg of AMD070 twice daily on days 2 through 9 (inclusive). Pharmacokinetic parameters of midazolam and dextromethorphan were assessed alone and in the presence of AMD070., Results: The mean AUC0-24 and Cmax of dextromethorphan increased 2.86-fold (2.20 to 5.10, 90% confidence interval [CI]) and 2.52-fold (1.99 to 4.24, 90% CI), respectively, in the presence of AMD070. Plasma AUC0-12 of midazolam increased 1.33-fold (1.15 to 1.61, 90% CI) without change in Cmax. The half-life did not change for both drugs, but significant, parallel decrease in apparent oral clearance and volume of distribution was observed., Conclusions: The data support an alteration in bioavailability due to an AMD070-mediated inhibition of presystemic metabolism, though an intestinal P-glycoprotein effect could also be contributing. Interactions between AMD070 with CYP3A4 and, especially, 2D6 substrates of clinical importance in HIV care should be further explored.

The polyunsaturated fatty acid docosahexaenoic acid (DHA) makes up approximately 50% of the lipid chains in the retinal rod outer segment disk membranes and a large fraction of the lipid chains in the membranes of neuronal tissues. There is an extensive literature concerned with the dietary requirements for essential fatty acids and the importance of DHA to human health, but relatively little research has been done on the physical properties of this important molecule. Using (1)H and (13)C MAS NMR measurements of dispersions of 1-palmitoyl-2-docosahexaenoyl-phosphatidylcholine in excess phosphate buffer, we have unambiguously assigned most of the resonances in both the (1)H and (13)C NMR spectra. We were able to use cross-polarization spectroscopy to follow the transfer of polarization from specific (1)H nuclei not only to their directly bonded (13)C but also to those (13)C that are in close proximity, even though they are not directly bonded. Cross-peaks in two-dimensional cross-polarization spectra revealed a close association between the choline headgroup and at least part of the DHA chain but not with the palmitate chain. Finally, we examined the dynamics of the different parts of this lipid molecule, using rotating frame spin-lattice relaxation measurements, and found that methylene groups of both chains experience important motions with correlation times in the 10-micros range, with those for the palmitate chain being approximately 50% longer than those of the DHA chain. The choline headgroup and the chain terminal groups have significantly shorter correlation times, and that part of the dipolar interaction that is fluctuating at these correlation times is significantly smaller for these groups than it is for the palmitate and DHA chain methylenes.

This study examines the effectiveness of a single, first-order Arrhenius process in accurately modelling the thermally induced changes in the optical properties, particularly the reduced scattering coefficient, mu(s)', and the absorption coefficient, mu(a), of ex vivo rat prostate. Recent work has shown that mu(s)' can increase as much as five-fold due to thermal coagulation, and the observed change in mu(s)' has been modelled well according to a first-order rate process in albumen. Conversely, optical property measurements conducted using pig liver suggest that this change in mu(s)' cannot suitably be described using a single rate parameter. In canine prostate, measurements have indicated that while the absorption coefficient varies with temperature, it does not do so according to first-order kinetics. A double integrating sphere system was used to measure the reflectance and transmittance of light at 810 nm through a thin sample of prostate. Using prostate samples collected from Sprague Dawley rats, optical properties were measured at a constant elevated temperature. Tissue samples were measured over the range 54-83 degrees C. The optical properties of the sample were determined through comparison with reflectance and transmittance values predicted by a Monte Carlo simulation of light propagation in turbid media. A first order Arrhenius model was applied to the observed change in mu(s)' and mu(a) to determine the rate process parameters for thermal coagulation. The measured rate coefficients were Ea = (7.18 +/- 1.74) x 10(4) J mol(-1) and Afreq = 3.14 x 10(8) s(-1) for mu(s)'. It was determined that the change in mu(s)' is well described by a single first-order rate process. Similar analysis performed on the changes in mu(a) due to increased temperatures yielded Ea = (1.01 +/- 0.35) x 10(5) J mol(-1) and Afreq = 8.92 x 10(12) s(-1). The results for mu(a) suggest that the Arrhenius model may be applicable to the changes in absorption.