To investigate time trends in incidence rates of first-time diagnosed attention-deficit/hyperactivity disorder (ADHD) in a nationwide sample aged 4-65 years across 16 years and identify potential ...contributing factors to these time trends.
Incidence rates of first-time diagnosed ADHD based on ICD-10 criteria in Danish psychiatric hospitals per 100,000 person years (PY) were calculated for the total population, the 2 sexes, and 4 age groups using data from the Danish Psychiatric Central Research Registry and annual census data. Time trends and the role of contributing factors were analyzed and identified using joinpoint regression procedures by calculating annual percent changes for the time period 1995-2010.
A total of 20,281 patients were diagnosed with ADHD and incidence rates increased from 7.3 to 91.2 per 100,000 PY during the study period. Joinpoint analysis suggested that incidence rates for diagnosed ADHD rapidly increased from 1998 to 2002, peaked from 2002 to 2008, and slowed down from 2008 to 2010. Contributing factors to the observed time trends were a general increase in patients seen in psychiatry for any mental disorder and an increased awareness and recognition of ADHD in females, adolescents, and adults.
These results provide empirical data needed in the public and professional debate often based on theoretical rather than empirical arguments. Results support the notion of increasing incidence rates of diagnosed ADHD and identify that contributing factors are a general increase in the number of patients assessed in psychiatry and an increased recognition of females, adolescents, and adults with ADHD.
The role of cytokines in regulation of hematopoietic stem cells (HSCs) remains poorly understood. Herein we demonstrate that thrombopoietin (THPO) and its receptor, MPL, are critically involved in ...postnatal steady-state HSC maintenance, reflected in a 150-fold reduction of HSCs in adult Thpo(-/-) mice. Further, whereas THPO and MPL proved not required for fetal HSC expansion, HSC expansion posttransplantation was highly MPL and THPO dependent. The distinct role of THPO in postnatal HSC maintenance is accompanied by accelerated HSC cell-cycle kinetics in Thpo(-/-) mice and reduced expression of the cyclin-dependent kinase inhibitors p57(Kip2) and p19(INK4D) as well as multiple Hox transcription factors. Although also predicted to be an HSC viability factor, BCL2 failed to rescue the HSC deficiency of Thpo(-/-) mice. Thus, THPO regulates posttransplantation HSC expansion as well as the maintenance of adult quiescent HSCs, of critical importance to avoid postnatal HSC exhaustion.
Caffeine, a non-selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known ...both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses.
Female Sprague-Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non-implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross-over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus.
A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: -1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine-treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR
was found in the choroid plexus.
This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted.
Background and Purpose
Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, ...the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate.
Experimental Approach
Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross‐over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT‐qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions.
Key Results
We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24‐h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium‐dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes.
Conclusions and Implications
Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.
The requirement of a childhood onset has always been a key criterion for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adults, but recently this requirement has become ...surrounded by controversy.
To investigate whether impaired young adults with ADHD symptoms always have a childhood-onset disorder in a population-based longitudinal study.
Participants belonged to the 1993 Pelotas Birth Cohort Study, including 5249 individuals born in Pelotas, Brazil, in 1993. They were followed up to 18 to 19 years of age, with 81.3% retention. The data analysis was performed between August 8, 2015, and February 5, 2016.
The ADHD status was first ascertained at 11 years of age using a screening instrument (hyperactivity subscale of the Strength and Difficulties Questionnaire) calibrated for a DSM-IV ADHD diagnosis based on clinical interviews with parents using the Development and Well-Being Assessment. At 18 to 19 years of age, ADHD diagnosis was derived using DSM-5 criteria, except age at onset. We estimated the overlap between these groups assessed at 11 and 18 to 19 years of age and the rates of markers of impairment in these 2 groups compared with those without ADHD.
At 11 years of age, childhood ADHD (C-ADHD) was present in 393 individuals (8.9%). At 18 to 19 years of age, 492 individuals (12.2%) fulfilled all DSM-5 criteria for young adult ADHD (YA-ADHD), except age at onset. After comorbidities were excluded, the prevalence of YA-ADHD without comorbidities decreased to 256 individuals (6.3%). Children with C-ADHD had a male preponderance not observed among children without ADHD (251 63.9% vs 1930 47.9% male, P < .001), whereas the YA-ADHD group had a female preponderance (192 39.0% vs 1786 50.4% male, P < .001). Both groups had increased levels of impairment in adulthood, as measured by traffic incidents, criminal behavior, incarceration, suicide attempts, and comorbidities. However, only 60 children (17.2%) with ADHD continued to have ADHD as young adults, and only 60 young adults (12.6%) with ADHD had the disorder in childhood.
The findings of this study do not support the assumption that adulthood ADHD is necessarily a continuation of childhood ADHD. Rather, they suggest the existence of 2 syndromes that have distinct developmental trajectories.
In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system ...are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis.
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•Embryonic lymphoid lineage restriction initiates prior to emergence of definitive HSC•Embryonic lymphoid-primed progenitors have immune-restricted lymphomyeloid potential•Embryonic lymphoid-primed progenitors contribute to myelo- and lymphopoiesis in utero•Lympho-myelo immune restriction is an early-fate decision in embryonic hematopoiesis
An immune-restricted lymphomyeloid-primed progenitor with the capacity to contribute to both myeloid and lymphoid lineages in the developing embryo emerges prior to definitive HSCs.
All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict ...separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1+c-kit+Flt3- HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin-Sca-1+c-kit+CD34+Flt3+ cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.
The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second ...throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output.
Background
We investigated the mortality risk associated with the initiation of antipsychotic treatment among patients with dementia and whether comorbidities related to the cardiovascular system and ...diabetes interact with antipsychotic treatment to increase the mortality risk beyond the risk of death independently associated with antipsychotics and comorbidity alone.
Methods
We designed a matched cohort study using nationwide registry data. All Danish residents aged 65–95 years diagnosed with dementia between 2009 and 2014 were included. Dementia was assessed as a first‐time registered dementia diagnosis in the Danish National Patient Register or the Danish Psychiatric Central Research Register and/or a first‐time prescription for antidementia medication. Patients exposed to antipsychotics were matched with up to three unexposed patients. Cox proportional hazards models were used to compare rates of death within 180 days after the initiation of antipsychotic treatment. The models were adjusted for potential confounders. Analyses were stratified for diabetes, heart disease, and cerebrovascular disease, and we calculated the relative excess risk due to interaction (RERI).
Results
The study cohort included 8244 exposed patients and 24,730 unexposed patients. A total of 5938 patients died during the first 180 days of follow‐up. Patients exposed to antipsychotics had a significantly higher adjusted risk of death (hazard ratio: 1.35, 95% confidence interval: 1.27–1.43) than unexposed patients. Crude mortality rates were higher among patients with heart disease and diabetes when antipsychotic treatment was initiated compared with patients without comorbidities. Relative risk estimates did not differ between patients with and without heart disease, cerebrovascular disease, and diabetes, and RERI suggested no positive additive interaction. Risk analysis suggested higher mortality in patients without cerebrovascular disease who initiated antipsychotics.
Conclusion
This nationwide study adds to the evidence that antipsychotic treatment is associated with increased mortality and suggests that attention should be paid to all initiators of antipsychotics irrespective of cardiovascular disease and diabetes.
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