Age-associated systemic factors change central and peripheral immunity in adult male mice.

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.

A validated Screening instrument for Child Abuse and Neglect (SCAN) at the emergency department.

The objective of this study is to develop and validate a screening instrument for the recognition of child maltreatment in the emergency department (ED). Existing data on screening questions and outcomes (diagnosis of child maltreatment) from three large observational screening studies at eight different EDs in the Netherlands were harmonized. A multivariate logistic regression was performed to develop the Screening instrument for Child Abuse and Neglect (SCAN). The SCAN was validated by performing a cross-validation and calculating the discriminative ability. A total of 24,963 patients were included. Out of the potential screening questions the following questions were included in the final instrument: is the injury compatible with the history, and does it correspond to the child's developmental level? (aOR 10.40, 95% CI 5.69-19.02), was there an unnecessary delay in seeking medical help? (aOR 3.45, 95% CI 1.73-6.88) and is the behaviour/interaction of the child and parents (carers) appropriate? (aOR 14.67, 95% CI 7.93-27.13). The SCAN had a pooled AUC of 0.75 (95% CI 0.63-0.87) in the cross-validation. The question "Are there other signals that make you doubt the safety of the child and/or family?" (available in only one of the original datasets, OR 182.9; 95% CI 102.3-327.4) was by consensus added to the final SCAN. CONCLUSION: This validated and brief Screening instrument for Child Abuse and Neglect (SCAN) is designed to improve early recognition of child maltreatment in the ED. A positive screening result of the SCAN warrants a thorough work-up for child maltreatment, including a top-toe examination, if necessary additional diagnostics and adequate safety measures. WHAT IS KNOWN: • Screening instruments increase the detection of possible cases of child maltreatment in the emergency department and support health care professionals to identify these cases. • The application of different screening instruments led to the need for one brief validated instrument. WHAT IS NEW: • This study presents a validated and brief Screening instrument for Child Abuse and Neglect (SCAN), consisting of four questions. • The SCAN supports professionals in detecting signals of child maltreatment, and a positive screening result should lead to a thorough work-up, including a top-toe examination, complete history, additional diagnostic tests and consultation of a child abuse expert.

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.

Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands - A Questionnaire Study Among Anaesthesiologists, Neurologists and Clinical Geneticists.

BACKGROUND: Patients with neuromuscular disorders are at increased risk of suffering perioperative complications. Current knowledge concerning this topic is based on small retrospective studies and expert opinion. Therefore, an individualized multidisciplinary approach to perioperative anaesthesia planning is invaluable to anticipate difficulties and to optimize outcomes. OBJECTIVE: To evaluate current practice regarding preoperative counselling and perioperative care of neuromuscular patients, with the aim to facilitate standardization and improvement of perioperative care for neuromuscular patients. METHODS: A questionnaire-based cross-sectional, observational study was conducted between July, 1st 2020 and December, 31st, 2020 in Dutch anaesthesia, neurology and clinical genetics departments. Main outcome measures were 1.) frequency of consultation requests for neuromuscular patients prior to surgery, 2.) current practice, educational activities and departmental approach to this topic and 3.) preoperative counselling of neuromuscular patients. RESULTS: A total of 83 departments participated. Consultations for a neuromuscular patient scheduled for anaesthesia were requested from anaesthesia and neurology department only infrequently. Local guidelines concerning perioperative care of neuromuscular patients were available in 36.4% of the participating departments. Quality of specific training for residents and staff anaesthetists/neurologists covering perioperative care of neuromuscular patients was rated as 'very good' or 'good' by 42.9%. Neuromuscular patients scheduled for surgery were 'always' or 'often' discussed in multidisciplinary meetings involving anaesthesiologists and neurologists in 20.8% of the participating departments. CONCLUSION: Perioperative care for neuromuscular patients in the Netherlands is highly variable and might benefit from guidelines, education of health care professionals and multidisciplinary meetings between anaesthesiologists and neurologists on a regular basis.

Having an eye for myotonic dystrophy: A qualitative study on experiences and support needs in myotonic dystrophy type 1 patients with a diagnostic delay after early-onset cataract.

Myotonic dystrophy type 1 is a neuromuscular disorder affecting multiple organ systems and is characterized by a variety of clinical presentations. Anticipation leads to an earlier and more severe phenotype in subsequent generations. Early-onset cataract is a common initial manifestation of the late or adult-onset type of myotonic dystrophy 1. Due to its multicausal nature, early-onset cataract is often not recognized as a feature of this disease, leading to diagnostic delay resulting in consequences for successive generations, treatment and counseling. A qualitative study with semi-structured interviews was performed with purposive sampling of eight participants with myotonic dystrophy type 1 and early-onset cataract to investigate the physical and psychosocial consequences experienced due to diagnostic delay. Prior to the early-onset cataract, all participants experienced other multisystem symptoms that could have been explained by myotonic dystrophy. The diagnostic delay had severe hereditary consequences: a subsequent generation with more severely affected (grand)children was born resulting in large emotional burden for the patients. To conclude, early-onset cataract is a warning sign and ophthalmologists play a crucial role in the early detection of myotonic dystrophy type 1 by recognizing this symptom and preventing the birth of severely affected children leading to emotional and psychosocial consequences.

Socio-economic aspects of improved sanitation in slums: a review.

This socio-economic review provides an overview of the sanitation crisis in slum areas, and re-emphasizes the importance of sanitation. It highlights a lack of recognition of actual drivers for sanitation improvements, and the complexities in the provision of sanitation services in the context of urban slums with a mix of tenants and landlords. It elaborates how the drivers of demand for sanitation outlined in contemporary research are not universal but are rather context specific. The authors point out specific knowledge gaps for future research; for example, the need to establish a scientific basis for context-specific drivers of demand for sanitation improvements in slums, and a better understanding of associated complexities in order to set boundary conditions for achieving desired improvements.

Factor V Leiden mutation does not affect coagulopathy or outcome in lethal H1N1 influenza.

Influenza A is a major cause of mortality. Knowledge on coagulation activation in influenza infection is limited. The factor V Leiden (FVL) mutation is possibly subject to positive selection pressure. It is unknown whether this mutation impacts on the outcome of severe influenza. In the present study, the effect of lethal influenza on pulmonary and systemic coagulation activation and whether or not FVL mutation alters coagulation activation in and the course of lethal influenza, was determined. Wild-type mice, and mice heterozygous or homozygous for FVL were infected intranasally with a lethal dose of H1N1 (haemagglutinin 1 and neuraminidase 1) influenza A. Mice were sacrificed after 48 or 96 h for determination of coagulation activation, histopathology, pulmonary inflammatory parameters and viral load, or were observed in a survival study. Extensive local and systemic coagulation activation during lethal influenza was demonstrated by increased lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products, and by pulmonary fibrin deposition. FVL mutation did not influence the procoagulant response, lung histopathology or survival. FVL mice demonstrated elevated viral loads 48 h after infection. In conclusion, coagulation is activated locally and systemically during lethal murine influenza A infection. The FVL mutation does not influence coagulation activation, lung inflammation or survival in lethal influenza A.

Pleural Enterococcus faecalis empyema: an unusual case.

A 63-year-old female patient was admitted to the department of neurology following an acute ischemic infarction of the right medial cerebral artery. She developed fever, respiratory failure, and hypotension and had to be transferred to the intensive care unit (ICU) for intubation and mechanical ventilation. Chest X-ray showed increased density of the complete right hemi-thorax, indicative of massive pleural effusion. Chest tube drainage produced 1.5 l of pus in 1 h. Cultures revealed growth of Enterococcus faecalis. The patient was treated with amoxicillin and clavulanic acid with good clinical response. Enterococci very rarely cause spontaneous pleural empyema. The natural resistance of enterococci to several types of antibiotics can lead to selection of enterococci as seen in other clinical studies and may lead to this unusual clinical consequence.

Functional impairments, fatigue and quality of life in RYR1-related myopathies: A questionnaire study.

Mutations in RYR1 are a common genetic cause of non-dystrophic neuromuscular disorders. To obtain baseline data concerning the prevalence of fatigue, the psychological disease burden and quality of life associated with these common conditions, we performed a questionnaire study. Seventy-two patients were included in this study, 33 with a congenital myopathy and 39 with malignant hyperthermia or exertional rhabdomyolysis. Our results showed that patients with RYR1-related myopathies have more functional impairments and significant chronic fatigue compared to healthy controls, with almost half of patients being severely fatigued. Whilst fatigue, pain and associated physical and social difficulties were more pronounced in those with permanent phenotypes, individuals with intermittent phenotypes also scored higher in all relevant categories compared to healthy controls. These findings indicate that RYR1-related myopathies, despite being often considered relatively mild conditions, are nevertheless associated with severe fatigue and functional limitations, resulting in substantial loss of quality of life. Moreover, milder but in essence similar findings in patients with RYR1-related malignant hyperthermia and rhabdomyolysis suggest that those phenotypes are not truly episodic but in fact associated with a substantial permanent disease burden. These preliminary data should help to design more comprehensive quality of life studies to inform standards of care.

Perceptual development of phoneme contrasts: how sensitivity changes along acoustic dimensions that contrast phoneme categories.

Listeners discriminate acoustic differences between phoneme categories at a higher level than similarly sized differences within phoneme categories. The question this paper aims to answer is how this pattern in perceptual sensitivity develops along an acoustic dimension that contrasts two non-native speech sounds: through acquired distinctiveness, through acquired similarity, or through a combination of the two. A pretest-training-post-test experiment was designed to study perceptual development directly, i.e., by including (i) a discrimination task to measure perceptual sensitivity, (ii) a transfer test to ensure language learning instead of stimulus learning, and (iii) a control group to exclude task repetition as an explanation of improvement. It is shown that the typical peak in perceptual sensitivity near a phoneme boundary that native listeners show is not found in relatively inexperienced language learners, despite their ability to classify a continuum in a nativelike way after short laboratory training. Experiment II indicates that a discrimination peak may be achieved by language learners, but only after much more language experience than short-term laboratory training can offer. Furthermore, reasons are given why classification improvement in the laboratory should not be taken as evidence for (i) increased discrimination of the newly learned phonemes and (ii) learning of phoneme representations.

Pre-post evaluation of effects of a titanium dioxide coating on environmental contamination of an intensive care unit: the TITANIC study.

BACKGROUND: Among patients admitted to European hospitals or intensive care units (ICUs), 5.7% and 19.5% will encounter healthcare-associated infections (HAIs), respectively, and antimicrobial resistance is emerging. As hospital surfaces are contaminated with potentially pathogenic bacteria, environmental cleanliness is an essential aspect to reduce HAIs. AIM: To address the efficacy of a titanium dioxide coating in reducing the microbial colonization of environmental surfaces in an ICU. METHODS: A prospective, controlled, single-centre pilot study was conducted to examine the effect of a titanium dioxide coating on the microbial colonization of surfaces in an ICU. During the pre- and post-intervention periods, surfaces were cultured with agar contact plates (BBL RODAC plates). Factors that were potentially influencing the bacterial colonization of surfaces were recorded. A repeated measurements analysis within a hierarchic multi-level framework was used to analyse the effect of the intervention, controlling for the explanatory variables. FINDINGS: The mean ratio for the total number of colony-forming units (cfus) in a room between the pre- and post-intervention periods was 0.86 (standard deviation 0.57). The optimal model included the following explanatory variables: intervention (P=0.065), week (P=0.002), culture surfaces (P<0.001), ICU room (P=0.039), and interaction between intervention and week (P=0.002) and between week and culture surfaces (P=0.031). The effect of the intervention on the number of cfus from all culture plates in Week 4 between the pre- and post-intervention periods was -0.47 (95% confidence interval -0.24 to - 0.70). CONCLUSION: This study found that a titanium dioxide coating had no effect on the microbial colonization of surfaces in an ICU.

Severe Yersinia enterocolitica sepsis after blood transfusion.

A 23-year-old male received multiple blood transfusions following complicated thoracic surgery. He developed progressive haemorrhagic shock and multiple organ dysfunction syndrome. Blood cultures grew Yersinia enterocolitica. The patient was proven negative for Yersinia enterocolitica; however, one of the donors was found to be positive. Although strict selection of blood transfusion donors is warranted in the Netherlands, contamination of blood components may still occur and therefore should be considered whenever adverse events occur during or after blood transfusion.

[Severe pneumonia from psittacosis in a bird-keeper]. / Ernstige pneumonie door papegaaienziekte bij een vogelhouder.

A 67-year-old man was admitted due to severe pneumonia. Initially he was treated with beta-lactam antibiotics and oxygen. However, he developed respiratory failure and was transferred to the intensive-care unit for mechanical ventilation. He was a bird-keeper who collected many species of exotic birds, including parrots. The diagnosis psittacosis (parrot fever) was confirmed serologically and by PCR on bronchoalveolar lavage fluid. PCR techniques lead to rapid diagnosis which allows for early treatment. The initial treatment of atypical pneumonia with ciprofloxacin failed. After the patient was treated with doxycycline 200 mg i.v. his clinical condition improved and he was cured. The patient was discharged from intensive care after 10 days when acute respiratory-distress syndrome and pericarditis had resolved. Psittacosis is seen sporadically in the Netherlands. It may be encountered more frequently among patients who have had contact with birds and should be considered in the differential diagnosis of atypical pneumonia.

[Pets are a risk for asplenic patients: Capnocytophaga canimorsus infection in an asplenic patient]. / Huisdieren zijn een risico voor patiënten zonder milt.

Post-splenectomy sepsis is a serious condition with high mortality rates. We present a case of a 64-year-old patient with a medical history of splenectomy who was referred to the Emergency Department with a fever, shivers, and an altered mental state. The symptoms had started twelve hours before. Upon arrival in the hospital the patient was tachypnoeic, hypotensive and febrile. Blood cultures were taken and broad-spectrum antibiotics were started. He was directly admitted to the Intensive Care Unit with severe sepsis of unknown aetiology. CT imaging did not reveal the source of the infection. A second medical history assessment revealed that the patient had engaged in play fighting with a dog two days previously, which left a superficial lesion on his arm. A Capnocytophaga canimorsus infection was deemed likely and antibiotics were switched to intravenous amoxicillin-clavulanic acid. Despite maximal support the patient's clinical condition deteriorated rapidly. The patient died from multi-organ failure fourteen hours after admission to the hospital.

[An integrated approach including paediatric and forensic medical expertise on suspicion of child abuse]. / Meer zekerheid bij vermoeden van kindermishandeling.

A false accusation of child abuse has a major impact on child and family. Conversely, a missed diagnosis of child abuse may have significant and lifelong consequences for the child. For health professionals the assessment of the nature of the injury and differentiating between accidental and inflicted injury, disease manifestation or a physiological phenomenon can be challenging. For adequate determination of the cause of injury, an integrated approach including paediatric knowledge and forensic medical expertise is essential. Therefore, a national expertise centre for child abuse (LECK) was established in the Netherlands in 2014. The first results of this integrated approach are described and illustrated with three case reports. Case A, a 7-month-old boy with an accidental humerus fracture. Case B, an 8-year-old boy with a false positive suspicion of child abuse who was eventually diagnosed with Henoch-Schönlein syndrome. Case C, boy of 3 months with bruises and a metaphyseal fracture of the femur, both highly suspected of being inflicted injury.

Reliability and validity of the pain observation scale for young children and the visual analogue scale in children with burns.

The aim of this study was to assess if the pain observation scale for young children (POCIS) and the visual analogue scale (VAS) are reliable and valid instruments to measure procedural and background pain in burned children aged 0-4 years. Burn care nurses (n=73) rated pain from 24 fragments of videotaped children during wound care procedures and during periods of rest using the POCIS and the VAS. Intraclass correlations were used to assess inter-rater and intra-rater reliability for the POCIS and the VAS. Internal consistency for POCIS was assessed by Cronbach's alpha. The POCIS has shown poor to moderate inter-rater reliability, moderate to good intra-rater reliability and an acceptable internal consistency. The VAS turned out to have poor inter-rater reliability and poor to moderate intra-rater reliability. Due to poor results of inter-rater reliability in both scales, construct validation is left undone until more acceptable results are obtained. Factors explaining the results are the large number of raters, the manner they were trained and a lack of variation between pain classes in video fragments. Although not all results were satisfying, an easy to use scale as POCIS has promising qualities and deserves further reliability research.

Endogenously formed norharman (beta-carboline) in platelet rich plasma obtained from porphyric rats.

Porphyria was induced in adult male Wistar rats starved for 24 hr by SC injection of 400 mg/kg allylisopropylacetamide (AIA). The presence of porphyria was shown by measuring excretion of delta-aminolevulinic acid (delta-ALA) and porphobilinogen (PBG) into the urine during 24 hr after AIA administration. Plasma levels of glycine, serine and of a number of other amino acids were decreased in porphyric rats as compared to controls. Intraperitoneal injection of 2 mmol/kg serine 24 hr after AIA administration was used as an animal model for an acute psychosis, by measuring catalepsy scores 30 min after serine injection. The concentration of 5 different beta-carbolines in platelet rich plasma (PRP) was measured using an HPLC-fluorometric method. An increase in the concentration of norharman (NH) in PRP, ranging from 0.57 nmoles/l in control rats to 1.88 nmoles/l in serine treated porphyric rats was found. The catalepsy duration was exponentially correlated with the NH concentrations in PRP. It is concluded that an elevated conversion of serine into glycine via serine hydroxymethyltransferase (SHMT) may be responsible for the enhanced NH biosynthesis.

Serine and glycine-induced catalepsy in porphyric rats: an animal model for psychosis?

It was investigated whether an increased demand for glycine, as postulated to occur in patients who have suffered from episodic psychoses accompanied by multiple perceptual distortions, could evoke psychotic reactions. Catalepsy was used as a measure for psychosis and was observed after injection of serine or glycine in porphyric rats. Catalepsy was was shown to occur after serine as well as glycine administration in 2-allyl-2-isopropylacetamide (AIA) pretreated rats, while in lead (Pb) + phenobarbital pretreated rats only glycine was effective. Administration of AIA to rats resulted in a strongly enhanced excretion of porphobilinogen (PBG) in urine, while Pb + phenobarbital pretreated rats showed increased excretion of delta-aminolevulinic acid (delta-ALA). The Pb + phenobarbital pretreated animals showed elevated serine plasma levels and lowered glycine plasma levels 18 hours after injection, while no significant differences in plasma levels of these amino acids were found 24 hours after AIA administration. In AIA or saline pretreated animals, but not in those pretreated with Pb + phenobarbital, glycine formation from serine was elevated. It is concluded that the present animal model can be used to investigate episodic psychoses.