With the wide access to studies of selected gene expressions in transgenic animals, mice have become the dominant species as cerebral disease models. Many of these studies are performed on animals of ...not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain maturation requires at least three months in rats, there is a clear need to discern the corresponding minimal animal age to provide an “adult brain” in mice in order to avoid modulation of disease progression/therapy studies by ongoing developmental changes. For this purpose, we have studied anatomical brain alterations of mice during their first six months of age. Using T2-weighted and diffusion-weighted MRI, structural and volume changes of the brain were identified and compared with histological analysis of myelination. Mouse brain volume was found to be almost stable already at three weeks, but cortex thickness kept decreasing continuously with maximal changes during the first three months. Myelination is still increasing between three and six months, although most dramatic changes are over by three months. While our results emphasize that mice should be at least three months old when adult animals are needed for brain studies, preferred choice of one particular metric for future investigation goals will result in somewhat varying age windows of stabilization.
•Mouse brain volume is already stable at three weeks of age.•Mouse brain cortex continues to flatten till three months of age.•Myelination in mouse brain still increases till three months of age.•Mice need to be three months or older, when brain studies are to be done on adult animals.
Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy ...remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.
Neurological complications in COVID-19 patients admitted to an intensive care unit (ICU) have been previously reported. As the pandemic progressed, therapeutic strategies were tailored to new ...insights. This study describes the incidence, outcome, and types of reported neurological complications in invasively mechanically ventilated (IMV) COVID-19 patients in relation to three periods during the pandemic.
IMV COVID-19 ICU patients from the Dutch Maastricht Intensive Care COVID (MaastrICCht) cohort were included in a single-center study (March 2020 – October 2021). Demographic, clinical, and follow-up data were collected. Electronic medical records were screened for neurological complications during hospitalization. Three distinct periods (P1, P2, P3) were defined, corresponding to periods with high hospitalization rates. ICU survivors with and without reported neurological complications were compared in an exploratory analysis.
IMV COVID-19 ICU patients (n=324; median age 64 IQR 57–72 years; 238 males (73.5%)) were stratified into P1 (n=94), P2 (n=138), and P3 (n=92). ICU mortality did not significantly change over time (P1=38.3%; P2=41.3%; P3=37.0%; p=.787). The incidence of reported neurological complications during ICU admission gradually decreased over the periods (P1=29.8%; P2=24.6%; P3=18.5%; p=.028). Encephalopathy/delirium (48/324 (14.8%)) and ICU-acquired weakness (32/324 (9.9%)) were most frequently reported and associated with ICU treatment intensity. ICU survivors with neurological complications (n=53) were older (p=.025), predominantly male (p=.037), and had a longer duration of IMV (p<.001) and ICU stay (p<.001), compared to survivors without neurological complications (n=132). A multivariable analysis revealed that only age was independently associated with the occurrence of neurological complications (ORadj=1.0541; 95% CI=1.0171–1.0925; p=.004). Health-related quality-of-life at follow-up was not significantly different between survivors with and without neurological complications (n = 82, p=.054).
A high but decreasing incidence of neurological complications was reported during three consecutive COVID-19 periods in IMV COVID-19 patients. Neurological complications were related to the intensity of ICU support and treatment, and associated with prolonged ICU stay, but did not lead to significantly worse reported health-related quality-of-life at follow-up.
•Neurological complications are common in mechanically ventilated COVID-19 patients.•The most common neurological complications are delirium and ICU-acquired weakness.•The incidence of neurological complications was highest early in the pandemic.•Neurological complications were related to the intensity of ICU support/treatment.
Metachromatic leukodystrophy (MLD) is a rare progressive neurological disorder, often accompanied by motor impairments that are challenging to treat. In this case series, we report the course of ...treatment with intrathecal baclofen (ITB), aimed at improving daily care and comfort in children and young adults with MLD. All patients with MLD in our centre on ITB treatment for a minimum of 6 months were included (n=10; 4 males, 6 females; mean age 10y 8mo range 6–24y). Eight patients had MLD with a predominant spastic movement disorder (sMLD) and two were mainly dyskinetic. Patients with sMLD were compared with matched patients with spastic cerebral palsy (CP). Complication rates related to ITB treatment were similar in both groups. ITB treatment course in the first 6 months after pump implantation appears to show more dose increase in most patients MLD, compared to patients with spastic CP. This may be due to the progressive disease in MLD. ITB is a feasible therapy to improve daily care and comfort in patients with MLD and should therefore be considered early.
What this paper adds
Intrathecal baclofen (ITB) is a feasible therapy to improve comfort and daily care in children and young people with metachromatic leukodystrophy (MLD).
In the first 6 months of ITB treatment, MLD seems to show more dose increase compared to spastic cerebral palsy.
Resumen
Baclofen intratecal en la leucodistrofia metacromática
La leucodistrofia metacromática (LDM) es una rara enfermedad neurológica progresiva, habitualmente acompañada de déficit motor de muy difícil abordaje. En esta serie de casos reportamos el curso del tratamiento con baclofen intratecal (BIT), con el fin de mejorar el cuidado diario y el bienestar en niños y adultos jóvenes con esta afectación. Todos los pacientes de nuestro centro portadores de LDM y en tratamiento con BIT fueron incluidos (n=10; 4 varones, 6 mujeres, edad medias 10 años 8 meses rango 6‐24 años). Ocho pacientes tenían una LDM con un desorden del movimiento predominantemente espástico (LDMesp) y dos eran predominantemente diskinética. Los pacientes con LDMesp fueron comparados con pacientes portadores de Parálisis Cerebral Infantil (PCI). Las ratios de complicaciones relacionados con el tratamiento con BIT fueron similares en ambos grupos. El curso del tratamiento con BIT en los primeros 6 meses luego de la implantación de la bomba aparentemente muestra un mayor aumento de la dosis en gran parte de los pacientes con LDM, comparado con los pacientes con PCI espástica. Esto podría deberse a las características progresivas de la LDM. El BIT es una terapia factible y mejora el bienestar y cuidado diario de los pacientes con LDM, y, debería por ello, ser considerada tempranamente como tratamiento.
Resumo
Baclofeno intratecal em leucodistrofia metacromática
A leucodistrofia metacromática (LDM) é uma desordem neurológica rara e progressiva, frequentemente acompanhada por deficiências motoras que são difíceis de tratar. Nesta série de casos, reportamos o curso do tratamento com baclofeno intratecal (BIT), com o objetivo de melhorar o cuidado diário e conforto em crianças e jovens com LDM. Todos os pacientes com LDM em nosso centro para tratamento com BIT por no mínimo 6 meses foram incluídos (n=10; 4 do sexo masculino, 6 do sexo feminino; média de idade 10a 8m variação 6–24a). Oito pacientes tinham LDM com desordem do movimento predominantemente espástica (eLDM) e dois eram predominantemente discinéticos. Pacientes com eLDM foram pareados com pacientes com paralisia cerebra (PC) espástica. As taxas de complicação relacionadas ao tratamento com BIT foram similares em ambos os grupos. O curso do tratamento com BIT nos primeiros 6 meses após implantação da bomba parece mostrar maior aumento de dose nos pacientes com LDM, comparados aos com PC espástica. Isso pode ser devido à doença progressiva em LDM. BIT é uma terapia viável para melhorar o cuidado diário e conforto em pacientes com LDM, e deve portanto ser considerado precocemente.
What this paper adds
Intrathecal baclofen (ITB) is a feasible therapy to improve comfort and daily care in children and young people with metachromatic leukodystrophy (MLD).
In the first 6 months of ITB treatment, MLD seems to show more dose increase compared to spastic cerebral palsy.
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Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients ...worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype–phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.
Apart from being a consequence of intimate partner violence (IPV), posttraumatic stress disorder (PTSD) can also be a risk factor for IPV revictimization. The current study examined how each of 4 ...PTSD symptom clusters (reexperiencing, arousal, avoidance, and numbing) related to revictimization in a sample of 156 female help‐seeking victims of IPV, recruited from various victim support services in the Netherlands. In addition, we hypothesized that victim‐perpetrated IPV would mediate the relation between PTSD symptomatology and IPV revictimization. Our results show that victims' PTSD reexperiencing symptoms predict revictimization of partner violence (d = .45 for physical IPV revictimization; d = .35 for psychological IPV revictimization); the other 3 PTSD symptom clusters were not related to IPV revictimization. Furthermore, victim‐perpetrated psychological IPV was found to partially mediate the relation between victims' PTSD reexperiencing symptoms and IPV revictimization (Z = 2.339, SE = 0.044, p = .019 for physical IPV revictimization, and Z = 2.197, SE = 0.038, p = .028 for psychological IPV revictimization). Findings indicate that IPV victims with higher levels of PTSD reexperiencing symptoms may be more likely to perpetrate psychological IPV themselves, which may put them at greater risk for receiving IPV in return. Based on these results, a focus on individual PTSD symptom clusters and victim behaviors seems relevant for practice and may contribute to a decrease in victims' risk for future IPV.
Objective
In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow ...remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients.
Methods
Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age‐matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t‐test, linear regression or the nonparametric Mann–Whitney U‐test was performed to evaluate differences between the transplanted, nontransplanted, and control group.
Results
In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti‐inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross‐correction to resident astrocytes and oligodendrocytes.
Interpretation
In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross‐correction of oligo‐ and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.
Molars of eight large herbivore species (Megaloceros giganteus, Cervus elaphus, Rangifer tarandus, Alces alces, Bison priscus, Ovibos moschatus, Coelodonta antiquitatis and Stephanorhinus ...kirchbergensis) were collected ex situ from Pleistocene and Holocene sands dredged in the North Sea, and from Dutch inland sites. Folds in many molars contained compacted masticated plant remains, and also microfossils. We identified pollen, spores, and non-pollen palynomorphs and discuss and interpret food preferences, represented flowering seasons, or parts of flowering seasons, and we discuss effects of changing vegetation composition in relation to climate and age of the molars, based on the pollen spectra. Various confounding factors have contributed to the recorded pollen composition, but nevertheless the pollen spectra show valuable aspects of vegetation composition, food choice, age, and landscapes, from subarctic open areas to interglacial forest. Ecological and statistical analysis of the results shows dietary differences between the mammal species analyzed.
•Folds in molars of Pleistocene and Holocene herbivores contain pollen and spores.•Pollen from molars shows vegetation types from subarctic to interglacial settings.•Pollen composition indicates diet variability within and between herbivore species.•Monospecific pollen aggregates provide valuable information about food choice.
OBJECTIVES:To assess frequency of gallbladder polyposis and carcinoma in metachromatic leukodystrophy (MLD).
METHODS:We evaluated 34 patients with MLD (average age 16.7 years, age range 2–39 years) ...screened for gallbladder abnormalities by ultrasound. In the case of cholecystectomy, findings at pathology were reviewed.
RESULTS:Only 8 of 34 patients (23%) had a normal gallbladder at ultrasound. Gallbladder polyps were visible in 8 patients (23%). Cholecystectomy was performed in 11 patients (32%). In these, pathology revealed various abnormalities, including hyperplastic polyps, intestinal metaplasia, prominent Rokitansky-Aschoff sinuses, and sulfatide storage.
CONCLUSIONS:Our results demonstrate that gallbladder involvement is the rule rather than the exception in MLD. The high prevalence of hyperplastic polyps, a known precancerous condition, and one death from gallbladder carcinoma at a young age suggest that MLD predisposes to neoplastic gallbladder abnormalities. As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early death.
Victims of intimate partner violence (IPV) are known to be at high risk for revictimization. Yet, to date, the mechanisms explaining the link between victimization and revictimization of IPV have not ...been extensively studied. In the present prospective study involving 74 female help-seeking victims of IPV, we investigated victim-related psychological mechanisms that may underlie this link. With this study, we aim to contribute to the development of theory addressing these psychological mechanisms and their role in explaining risk for IPV revictimization. Hypotheses regarding possibly relevant psychological mechanisms were derived from two conflicting approaches to IPV: the gender perspective, and the mutual IPV perspective. Results lend further support to the mutual IPV perspective, since our final prediction model indicates that victim-perpetrated IPV is an important risk factor for physical and psychological IPV revictimization. An avoidant attachment style shows to be a strong predictor as well, in particular for victims with high and average anger levels. Findings provide clear indications for risk assessment and treatment of IPV victims, and moreover offer opportunities to empower these victims in order to prevent future violence.
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