An MRI method for parcellating the human striatum into matrix and striosome compartments in vivo.

The mammalian striatum is comprised of intermingled tissue compartments, matrix and striosome. Though indistinguishable by routine histological techniques, matrix and striosome have distinct embryologic origins, afferent/efferent connections, surface protein expression, intra-striatal location, susceptibilities to injury, and functional roles in a range of animal behaviors. Distinguishing the compartments previously required post-mortem tissue and/or genetic manipulation; we aimed to identify matrix/striosome non-invasively in living humans. We used diffusion MRI (probabilistic tractography) to identify human striatal voxels with connectivity biased towards matrix-favoring or striosome-favoring regions (determined by prior animal tract-tracing studies). Segmented striatal compartments replicated the topological segregation and somatotopic organization identified in animal matrix/striosome studies. Of brain regions mapped in prior studies, our human brain data confirmed 93% of the compartment-selective structural connectivity demonstrated in animals. Test-retest assessment on repeat scans found a voxel classification error rate of 0.14%. Fractional anisotropy was significantly higher in matrix-like voxels, while mean diffusivity did not differ between the compartments. As mapped by the Talairach human brain atlas, 460 regions were significantly biased towards either matrix or striosome. Our method allows the study of striatal compartments in human health and disease, in vivo, for the first time.

A registration method for improving quantitative assessment in probabilistic diffusion tractography.

Diffusion MRI-based probabilistic tractography is a powerful tool for non-invasively investigating normal brain architecture and alterations in structural connectivity associated with disease states. Both voxelwise and region-of-interest methods of analysis are capable of integrating population differences in tract amplitude (streamline count or density), given proper alignment of the tracts of interest. However, quantification of tract differences (between groups, or longitudinally within individuals) has been hampered by two related features of white matter. First, it is unknown to what extent healthy individuals differ in the precise location of white matter tracts, and to what extent experimental factors influence perceived tract location. Second, white matter lacks the gross neuroanatomical features (e.g., gyri, histological subtyping) that make parcellation of grey matter plausible - determining where tracts "should" lie within larger white matter structures is difficult. Accurately quantifying tractographic connectivity between individuals is thus inherently linked to the difficulty of identifying and aligning precise tract location. Tractography is often utilized to study neurological diseases in which the precise structural and connectivity abnormalities are unknown, underscoring the importance of accounting for individual differences in tract location when evaluating the strength of structural connectivity. We set out to quantify spatial variance in tracts aligned through a standard, whole-brain registration method, and to assess the impact of location mismatch on groupwise assessments of tract amplitude. We then developed a method for tract alignment that enhances the existing standard whole brain registration, and then tested whether this method improved the reliability of groupwise contrasts. Specifically, we conducted seed-based probabilistic diffusion tractography from primary motor, supplementary motor, and visual cortices, projecting through the corpus callosum. Streamline counts decreased rapidly with movement from the tract center (-35% per millimeter); tract misalignment of a few millimeters caused substantial compromise of amplitude comparisons. Alignment of tracts "peak-to-peak" is essential for accurate amplitude comparisons. However, for all transcallosal tracts registered through the whole-brain method, the mean separation distance between an individual subject's tract and the average tract (3.2 mm) precluded accurate comparison: at this separation, tract amplitudes were reduced by 74% from peak value. In contrast, alignment of subcortical tracts (thalamo-putaminal, pallido-rubral) was substantially better than alignment for cortical tracts; whole-brain registration was sufficient for these subcortical tracts. We demonstrated that location mismatches in cortical tractography were sufficient to produce false positive and false negative amplitude estimates in both groupwise and longitudinal comparisons. We then showed that our new tract alignment method substantially reduced location mismatch and improved both reliability and statistical power of subsequent quantitative comparisons.

[Management of Uninhabitable Homes - Investigation of 186 Cases of Hoarding, Domestic Neglect and Squalor in Dortmund (Germany)]. / Der Dortmunder Vorschlag zum praktischen Vorgehen bei unbewohnbar gewordenen Wohnungen - Untersuchung von 186 Fällen von Vermüllung, Wohnungsverwahrlosung und pathologischem Horten (Messie-Syndrom).

OBJECTIVE: To develop an intervention concept for the management of uninhabitable homes. METHODS: Retrospective analysis of 186 cases of the community mental health service in Dortmund (Germany) presenting with a destitute situation of the domestic environment as core problem. RESULTS: All patients suffered from psychiatric illnesses, mainly from addiction (F1: 41%), psychosis (F2: 17%), depression (F3: 17%), and hoarding disorder (F63.8: 12%). Main socio-demographic characteristics of our sample are: middle age (45-65 years, 48%), male gender (73%), isolated situation (only 7% married, 84% living alone), normal schooling (only 4% without completion of schooling, 7% attended a school for special needs), after initial integration into employment nearly all patients suffered vocational disintegration (5% employed, 44% unemployment benefit, 7% welfare, 39% pension or invalidity benefit). Psychosocial interventions differed between the 4 main diagnostic groups: F1: treatment of dependence (rehab) and treatment of concomitant somatic diseases; F2: admission to a psychiatric hospital and implementation of guardianship; F3: mediation of conflicts with neighbours/landlords and implementation of guardianship; F63.8: direct practical help by members of the community mental health team and organisation of home help/waste disposal. In all diagnostic groups, acceptance of help was impaired due to social withdrawal, resistance and psychiatric symptoms. At 13%, compliance with help and interventions was lowest in the hoarder group (F1: 27%, F2: 26%, F3: 38%). Consequently, in this group the poor outcome categories "nothing accomplished" and "lost flat/eviction" were more frequent (44%, F1: 27%, F2: 26%, F3: 38%). CONCLUSIONS: Concurrent to the deterioration of the domestic situation, patients suffer vocational disintegration as well as family and social isolation. Uninhabitable homes occur in the course of various severe and chronic psychiatric diseases. They don't constitute a syndrome and they are not characteristic for one specific diagnosis. It is important to recognise the underlying psychiatric disease as diagnosis influences acceptance of help, choice of appropriate interventions, outcome and prognosis. Tab. 1 shows our suggestion for a diagnosis differentiated approach, relating appearance of the home and behaviour of the patient to diagnosis, appropriate interventions and prognosis. Hard to reach is the group of hoarders. Patients with a psychotic illness and with hoarding disorder require implementation of long-term outreach help in their homes.

[Management of Uninhabitable Homes - Investigation of 186 Cases of Hoarding, Domestic Neglect and Squalor in Dortmund (Germany)]. / Der Dortmunder Vorschlag zum praktischen Vorgehen bei unbewohnbar gewordenen Wohnungen - Untersuchung von 186 Fällen von Vermüllung, Wohnungsverwahrlosung und pathologischem Horten (Messie-Syndrom).

OBJECTIVE: To develop an intervention concept for the management of uninhabitable homes. METHODS: Retrospective analysis of 186 cases of the community mental health service in Dortmund (Germany) presenting with a destitute situation of the domestic environment as core problem. RESULTS: All patients suffered from psychiatric illnesses, mainly from addiction (F1: 41 %), psychosis (F2: 17 %), depression (F3: 17 %), and hoarding disorder (F63.8: 12 %). Main socio-demographic characteristics of our sample are: middle age (45-65 years, 48 %), male gender (73 %), isolated situation (only 7 % married, 84 % living alone), normal schooling (only 4 % without completion of schooling, 7 % attended a school for special needs), after initial integration into employment nearly all patients suffered vocational disintegration (5 % employed, 44 % unemployment benefit, 7 % welfare, 39 % pension or invalidity benefit).Psychosocial interventions differed between the 4 main diagnostic groups: F1: treatment of dependence (rehab) and treatment of concomitant somatic diseases; F2: admission to a psychiatric hospital and implementation of guardianship; F3: mediation of conflicts with neighbours/landlords and implementation of guardianship; F63.8: direct practical help by members of the community mental health team and organisation of home help/waste disposal. In all diagnostic groups, acceptance of help was impaired due to social withdrawal, resistance and psychiatric symptoms. At 13 %, compliance with help and interventions was lowest in the hoarder group (F1: 27 %, F2: 26 %, F3: 38 %). Consequently, in this group the poor outcome categories "nothing accomplished" and "lost flat/eviction" were more frequent (44 %, F1: 27 %, F2: 26 %, F3: 38 %). CONCLUSIONS: Concurrent to the deterioration of the domestic situation, patients suffer vocational disintegration as well as family and social isolation. Uninhabitable homes occur in the course of various severe and chronic psychiatric diseases. They don't constitute a syndrome and they are not characteristic for one specific diagnosis. It is important to recognise the underlying psychiatric disease as diagnosis influences acceptance of help, choice of appropriate interventions, outcome and prognosis. Tab. 1 shows our suggestion for a diagnosis differentiated approach, relating appearance of the home and behaviour of the patient to diagnosis, appropriate interventions and prognosis. Hard to reach is the group of hoarders. Patients with a psychotic illness and with hoarding disorder require implementation of long-term outreach help in their homes.

MIF is a common genetic determinant of COVID-19 symptomatic infection and severity.

BACKGROUND: Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. AIM: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. METHODS: This retrospective case-control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8,rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. RESULTS: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41-0.72], P < 0.0001]. Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR 2.87 [1.42-5.78], P = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, P = 0.01) and maximum CRP (r = 0.16, P = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. CONCLUSIONS: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection.

Astrotactin: a novel neuronal cell surface antigen that mediates neuron-astroglial interactions in cerebellar microcultures.

A microculture system for mouse cerebellar cells has been used to identify an immune activity, raised in rabbits against postnatal cerebellar cells, that blocks neuron-glial interactions in vitro. In the presence of blocking antibodies, stable neuron-glial contacts did not form and neuronal induction of glial process outgrowth did not occur. Subsequently, neurons were randomly arranged in the cultures rather than organized along the arms of astroglia. We have named the immune activity that blocks neuron-astroglial interactions anti-astrotactin. Partial purification of the anti-astrotactin blocking antibodies was obtained by cellular absorption with PC12 cells, a clonal cell line which expresses both the N-CAM and NILE (Ng-CAM, L1) glycoproteins. Subsequent absorption with purified cerebellar granule cells, but not with astroglial cells, removed the blocking activity, suggesting that the antigen(s) bound by blocking antibodies are neuronal. Immunoprecipitation of [35S]methionine- or [3H]fucose-radiolabeled Triton extracts of early postnatal cerebellar cells showed that the unabsorbed antiserum recognized a large number of proteins. Among these were bands with apparent molecular masses of N-CAM (180 and 140 kD) and NILE (230 kD). After absorption of the immune serum with PC12 cells, the number of bands recognized by the antiserum was reduced to a prominent band at 100 kD and a diffuse smear of material between 80 and 90 kD. The prominent band at 100 kD was removed by subsequent absorption of the immune serum with granule cells, a step which removed the blocking activity in the cerebellar microculture assay. Further evidence suggests that the astrotactin activity is missing or defective on granule cells from the neurological mutant mouse weaver, an animal that suffers a failure of glial-guided neuronal migration. When anti-astrotactin Fab fragments were pre-absorbed with weaver cerebellar neurons and then tested in the functional assay of neuron-glial interactions, the immune blocking activity was not removed. In contrast, wild-type cerebellar neurons removed the anti-astrotactin blocking activity under the same conditions. Subsequently, when [3H]fucose-radiolabeled Triton extracts of weaver and normal cells were immunoprecipitated with whole or PC12-absorbed anti-astrotactin antiserum, the intensity of the band at 100 kD was reduced by 95% in weaver cells.

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.

Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

Presynaptic cholinergic mechanisms in brain of aged rats with memory impairments.

Presynaptic cholinergic mechanisms were investigated in various brain regions of aged Fisher 344 rats with documented 24 hr retention deficits measured in a single-trial passive avoidance tasks. Sodium-dependent high affinity choline uptake was found to be decreased by 22% in hippocampus of 23-26 month old animals as compared to 6 month old controls. Prior depolarization of hippocampal or cortical synaptosomes with K+ resulted in stimulation of choline uptake which was similar in aged rats and young controls. No age-related differences were observed either in hippocampal, cortical, striatal acetylcholine or choline concentrations, or in the activity of choline acetyltransferase in hippocampus. Synthesis of acetylcholine in hippocampal and cortical slices under basal conditions, as well as under K+-stimulated concentrations, did not differ in the two age groups examined. These neurochemical findings are consistent with an age-related decrease in hippocampal cholinergic neuronal activity without an actual loss in cholinergic neuron number. It is further suggested that this reduction in cholinergic neuronal activity may be related to the deficit in cognitive performance observed in aged Fisher rats.

Adjuvant carboplatin treatment for seminoma clinical stage I.

The traditional adjuvant therapy for seminoma stage I is abdominal radiotherapy. Although the relapse rate ranges below 5% this treatment is challenged because concerns about adverse late effects are accumulating. Carboplatin is effective in metastatic seminoma and two pilot studies have indicated effectivity in the adjuvant setting also. As this drug is almost non-toxic in moderate doses it could be an ideal adjuvant treatment for seminoma stage I. A group of 82 patients, mean age 37.5 years (range 22-73 years), with histologically pure seminoma stage I, were given carboplatin 400 mg/m2 after orchiectomy; 60 patients received only one course of carboplatin, and 22 patients received two courses. The median time of observation is 24 months, ranging from 2 to 48 months, and 66 patients have a minimum follow-up of 1 year. There is one relapse so far. Toxicity is rather mild with no severe nausea/emesis. Mean platelet counts were 164/nl after 3 weeks and 208/nl after 4 weeks; thus, myelotoxicity was negligible. Gonadal toxicity was measured by serial follicle-stimulating hormone levels. The mean level was 11.4 U/l before treatment, and 16.2 U/l after 5 weeks, 17.3 U/l after 4 months, 14.5 U/l after 8 months and 13.5 U/l after 12 months. Thus, gonadal toxicity also appeared to be mild. In summary, the efficacies of adjuvant carboplatin and of abdominal radiotherapy seem to be identical. As carboplatin, in the dosage used, involves no severe acute side-effects and probably few late adverse effects, this regimen constitutes a promising new treatment option in seminoma patients stage I that deserves to be studied in randomized trials.

Loss of cholinergic neurons in the rat neocortex produces deficits in passive avoidance learning.

Bilateral kainic acid lesions of the ventral globus pallidus produced a significant and selective cortical decrease in choline acetyltransferase activity in the rat brain. When lesioned and control subjects were compared on performance of a step-through passive avoidance task, lesioned rats showed a marked retention deficit 24 hr after the initial training trial. This experimentally-induced memory deficit associated with a cortical cholinergic neuronal loss resembles the deficits in senile dementia of the Alzheimer type and may provide a useful animal model for studying the disease.

Absorption, metabolism and excretion of 14C-sultopride in the rat.

Rats received (14C)-Sultopride (St) in doses of 20 mg/kg by ip. and oral route. After ip.-administration, urinary elimination was 62% of administered dose in 72 hours, fecal excretion, 25% in 96 hours. Conversely, at 120 hours after oral administration, renal elimination was 46% and fecal elimination 34%. From these data 75% absorption of St in rat intestine may be deduced. From total excreted radioactivity (feces plus urine; ip. route) 35% is due to unchanged St. Seven metabolites were isolated from the urine. By comparison of isolated compounds with chemically synthesized putative metabolites using spectrophotometric and radiometric TLC scanning procedures 5 metabolites were identified: O-desmethylated St (DMSt; 20% of total radioactivity excreted), sulfon-desethylated St (SDESt; 13%), 5-pyrrolidine-oxo St (OSt; 3%), the product of hydrolysis of the central amide bond (MESS; 4%) and the secondary metabolite O-desmethyl-oxo St (ODMST; less than 1%). Two metabolites both minor (1% or less), remained unidentified. In guinea-pigs, metabolism of St leads almost exclusively to OSt while in mice, to DMSt.

[Extremely severe complication during ESWL caused by unsuspected asymptomatic pheochromocytoma]. / Schwere Komplikation während der ESWL durch ein unbekanntes, asymptomatisches Phäochromozytom.

In 0.1% the pheochromocytoma is the reason of a systemic hypertension. The symptoms of a persistent or paroxysmal hypertension with headache, excessive sweating and palpitations lead in 90% to the diagnosis pheochromocytoma. Very rarely a patient with pheochromocytoma may be asymptomatic. We introduce a 68-year-old man whose pheochromocytoma primarily rose up while ESWL and furthermore in anaesthesia. The problems to determine the diagnosis will be scrutinized as following.

[Improved tumor stent for internal palliative urinary diversion]. / Neu entwickelter Tumorstent zur internisierten palliativen Harnableitung.

The disadvantages of high flexible endoureteral stents (DJ) in case of tumorinduced extrinsic ureteral compression are due to an insufficient vertical stability of the used stents leading to stent-compression and consecutive hydro- or pyonephrosis. The new developed tumor-stent used in case of tumor-induced ureteral compression is available from 6 to 8 French in diameter and 24 to 32 cm in length. The corpus consists of a combination of high-stability plastics but is of sufficient elasticity in length. Both ends consist of extremely elastic J-parts guaranteeing an exact fixation. As against common DJ's with the same outside-diameter the new stent has a comparable interior diameter and compared to used "old" tumor stents promises a higher interior flow in case of extrinsic diseases. The application can be undertaken in well-known technique, needs no special instrumentation and no learning-curve. To date 52 stents at our urologic departments were placed without any problems, the latest remaining for 15 months. Tumor-induced compression or a higher rate of encrustation could not be seen. All patients tolerated these stents well. In our opinion the new stabilized endoureteral stent can be seen as a better solution instead of percutaneous nephrostomy or frequent stent changing in patients with tumor induced extrinsic ureteral compression.

[Convulsions during prophylactic use of mefloquine]. / Convulsies tijdens profylactisch gebruik van mefloquine.

In 1996 and 1997 the Dutch Pharmacovigilance Foundation LAREB received 6 reports of patients with convulsions that were attributed to prophylactic use of mefloquine. Five patients had no neurological history; one patient had a history of epilepsy but had not had any convulsion during the preceding 5-year period. The convulsions took place 1 to 23 days after start of the treatment with mefloquine. Because of the convulsions, the treatment was discontinued. The 4 patients with known follow-up showed full recovery with regard to the convulsions. The practising physician should be aware of the possible occurrence of rare neuropsychiatric adverse events like convulsions during the prophylactic use of mefloquine.

[Nocturnal back pain; a misdiagnosed symptom of spinal tumor]. / Nachtelijke (rug)pijn; het miskende weksignaal van een spinale tumor.

Four patients had nocturnal back pain or pain that worsened when lying down. In one of these, a 49-year-old man, the medical history mentioned a malignancy, as a result of which a spinal metastasis was suspected. In the other three patients, a 52-year old woman and two men aged 48 and 60 years, the nocturnal back pain and the back pain worsening when lying down was not recognised as indication of a spinal tumour. As objective neurological symptoms were not established at initial investigation, a long period of discomfort and frustration followed before the spinal tumour was diagnosed eventually. The importance of recognising these early complaints is stressed. Nowadays, MRI is the technique of choice to answer the question whether there is a space occupying process in the spine.