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.

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.

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.

[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.

[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.

[Water jet discotomy with microinvasive approach--in vitro testing and initial clinical aspects of a new procedure]. / Die Wasserstrahldiskotomie im mikroinvasiven Zugang--In-vitro-Testung und erste klinische Aspekte eines neuen Verfahrens.

AIM: The difference in consistence of the nucleus pulposus and the annulus fibrosus allows the water jet to selectively remove the nucleus in a closed vertebral disc at a certain pressure range. The aim of the study was to investigate the use of water jet cutting in microinvasive spinal surgery. METHODS: A comparison in terms of efficiency between the water jet and those of the laser and APLD (automatic percutaneous lumbar discotomy) was achieved by plastic reconstruction of the resected spaces using the in-vitro-model of the spinal column of young pigs. The in-vitro-study was followed by a prospective clinical study with 21 patients. RESULTS: The in-vitro-employment of the three different methods showed that there were no significant differences in volume of the removed nucleus material. During the use of the hydro jet at 50 bar and simultaneous suction the intradiscal pressure measured in vitro remained below 1 bar. Clinical tests on the 21 patients showed good to very good results in 71% of the patients tested (mean follow-up 5.8 months). No complications were found. As working mechanism the pure mechanical effect and the influence on chemical processes within the nucleus remain points for discussion. CONCLUSION: The current studies results demonstrate that hydrojet spinal surgery might be a safe new method for surgery of disc protrusion and contained prolapse.

Native pyeloureterostomy after kidney transplantation: experience in 48 cases.

Necrosis and stenosis of the ureter are severe complications after kidney transplantation and occur with mean incidence of 2,9-13,4 %. Several surgical techniques like simple nephrostomy or complex urinary tract reconstruction have been applied for repair. In this study, our experience with native pyeloureterostomy (NPUS) using the native ureter is presented. Between March 1978 and June 1996, 2,592 kidney transplantations were performed in our institution. In 48 patients (1,9%), secondary urinary tract reconstruction by NPUS was necessary. These patients were evaluated retrospectively by review of the case notes. At the time of operation the mean age was 45 +/- 14 years. Indications for NPUS were distal ureteral stenosis (n = 29), necrosis (n = 17), bleeding (n = 1) or iatrogenic lesion of the ureter (n = 1). The mean time period between transplantation and urinary tract reconstruction was 20 +/- 23 days (range: 1-90 days) for necrosis and 404 +/- 637 days (range: 14-2,385 days) for stenosis. A pyeloureterostomy was technically feasible in all patients using the recipient's ipsilateral ureter. In 40 out of 48 patients the graft developed a normal function postoperatively (follow up: 39 +/- 48 months). A graft nephrectomy was necessary only in one patient, because of complete pyelonnecrosis 6 days after NPUS. Two grafts were lost due to acute rejection. Data of five patients were not available > 15 years after successful reconstruction. We can conclude that NPUS is a safe and simple rescue technique for the treatment of distal ureteral complications after kidney transplantation. Therefore, this technique should be the therapy of choice when secondary reconstruction by re-ureteroneocystostomy is not possible.

Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett's esophagus.

AIM: The hypothesis that colonization with cagA(+) Helicobacter pylori strains protects against the development of gastroesophageal reflux disease (GERD) and its complications is tested. METHODS: Patients with reflux esophagitis and Barrett's esophagus were studied. Antral biopsy specimens were obtained for detection of H. pylori. A serum sample was obtained for determination of IgG antibodies to H. pylori and to the CagA protein. RESULTS: 736 patients were studied. 118 patients had reflux esophagitis, 36 had Barrett's esophagus, 108 had hiatal hernia without signs of inflammation (the reflux group), and 20 patients had esophageal or stomach cancer. The remaining 454 patients had no signs of GERD. The 262 patients with reflux disease had a significantly lower prevalence of H. pylori (34.9%) than the 454 controls (54.6%; p<0. 001). Among 310 H. pylori-positive patients from whom serum was available, colonization with cagA(+) strains was detected in 59% in the control group versus 35% in the reflux group (p<0.001). CONCLUSION: Patients with reflux esophagitis and Barrett's esophagus have a significantly lower prevalence of H. pylori colonization than controls, in particular of the cagA(+) type. These data suggest that colonization with cagA(+) H. pylori strains may be protective against the development of GERD

Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient?

OBJECTIVES: Adjuvant radiotherapy produces excellent disease-free rates in clinical Stage I seminoma. However, concern is growing about side effects and late hazards of this treatment. Carboplatin has been suggested to supplant radiotherapy. To date, there is little experience with this drug in the adjuvant treatment of seminoma. In particular, it is unclear whether one or two courses should be administered. METHODS: In a nonrandomized study, 125 patients with pure clinical Stage I seminoma were given adjuvant carboplatin treatment (400 mg/m2). Ninety-three patients received one course and 32 two courses. The median follow-up time was 48 months. To assess gonadal toxicity, serial measurements of follicle-stimulating hormone (FSH) levels were done. To assess myelotoxicity, platelet counts at 3 and 4 weeks after treatment were monitored. RESULTS: There were no relapses after two courses of carboplatin. After one course of carboplatin, eight relapses occurred (8.6%; 95% confidence interval [CI] 3.79% to 16.2%). All the relapses were located in the para-aortic region, and all the patients were rescued with cisplatin-based chemotherapy. The median time to recurrence was 16 months. The 5-year actuarial progression-free survival rate after one course was 91.1% (95% CI 85.25% to 97.01%). Younger patients (age groups: less than 30 years and 31 to 38 years) had relapses more frequently (P = 0.038) than those in the older age group (greater than 38 years). After 3 weeks, 32% of the patients had platelet counts below 150/nL. The median FSH level increased immediately after treatment, reaching a peak of 13.6 U/L. After 20 months, the median FSH level had returned to the normal range. CONCLUSIONS: One adjuvant course of carboplatin was associated with low myelotoxicity and low gonadal toxicity; however, the recurrence rate was almost 9% and thus unsatisfactory. After two courses of carboplatin, no relapse was observed. Thus, the two-course regimen of carboplatin appears to be equivalent to radiotherapy, and because of its favorable toxicity profile, this regimen should be investigated in randomized trials.

[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.