Body mass index and Mini Nutritional Assessment-Short Form as predictors of in-geriatric hospital mortality in older adults with COVID-19.

BACKGROUND & AIMS: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19. METHODS: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression. RESULTS: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMI<18.5 increased the risk of in-hospital mortality in COVID-19 patients (odds ratio [OR] = 2.30; confidence interval [CI] = 1.17-4.31). Overweight and obesity were not associated with in-hospital mortality. Malnutrition; i.e. MNA-SF 0-7 points, increased the risk of in-hospital mortality in patients treated for COVID-19 (OR = 2.03; CI = 1.16-3.68) and other causes (OR = 6.01; CI = 2.73-15.91). CONCLUSIONS: Our results indicate that obesity is not a risk factor for very old patients with COVID-19, but emphasize the role of underweight and malnutrition for in-hospital mortality in geriatric patients with COVID-19.

Markers of pluripotency and differentiation in human neural precursor cells derived from embryonic stem cells and CNS tissue.

Cell transplantation therapies for central nervous system (CNS) deficits such as spinal cord injury (SCI) have been shown to be effective in several animal models. One cell type that has been transplanted is neural precursor cells (NPCs), for which there are several possible sources. We have studied NPCs derived from human embryonic stem cells (hESCs) and human fetal CNS tissue (hfNPCs), cultured as neurospheres, and the expression of pluripotency and neural genes during neural induction and in vitro differentiation. mRNA for the pluripotency markers Nanog, Oct-4, Gdf3, and DNMT3b were downregulated during neural differentiation of hESCs. mRNA for these markers was found in nonpluripotent hfNPC at higher levels compared to hESC-NPCs. However, Oct-4 protein was found in hESC-NPCs after 8 weeks of culture, but not in hfNPCs. Similarly, SSEA-4 and CD326 were only found in hESC-NPCs. NPCs from both sources differentiated as expected to cells with typical features of neurons and astrocytes. The expressions of neuronal markers in hESC-NPCs were affected by the composition of cell culture medium, while this did not affect hfNPCs. Transplantation of hESC-NPC or hfNPC neurospheres into immunodeficient mouse testis or subcutaneous tissue did not result in tumor formation. In contrast, typical teratomas appeared in all animals after transplantation of hESC-NPCs to injured or noninjured spinal cords of immunodeficient rats. Our data show that transplantation to the subcutaneous tissue or the testes of immunodeficient mice is not a reliable method for evaluation of the tumor risk of remaining pluripotent cells in grafts.

X chromosome inactivation in females with multiple sclerosis.

The aetiology of multiple sclerosis (MS) is unknown. Autoimmune mechanisms are most probably involved. Loss of immunological tolerance to self-antigens is a common feature of autoimmune disorders. Response to X-linked self-antigens could be influenced by X-chromosome inactivation, and contribute to the gender bias observed in autoimmune disorders. Previous studies have indicated an association between skewed X inactivation and autoimmune thyroid disease and scleroderma. To investigate a potential role of X inactivation in MS, we compared the X-inactivation pattern in 568 female MS patients with controls. We found no difference in degree of skewing between patients (median 64%) and controls (median 65%) (P = 0.474). The X-inactivation pattern did thus not explain the female predominance of MS patients in general. As the aetiology of different subgroups of MS may differ, patients were grouped according to disease course: relapsing-remitting (RR-MS), secondary progressive (SP-MS) and primary progressive (PP-MS). A comparison of the X-inactivation pattern between subgroups indicated a possible difference in degree of skewing between patients with a progressive versus a relapsing course (P = 0.05).

The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients.

The human leucocyte antigen (HLA) class II haplotype DRB1*15-DQB1*06 (DR15-DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal-Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort.

A follow-up study of Nordic multiple sclerosis candidate gene regions.

In this study, the results from three Nordic linkage disequilibrium screens in multiple sclerosis (MS) were investigated, in a new sample set of 314 Nordic MS trios from Denmark, Norway, Sweden and Iceland. Among 30 non-HLA and two HLA microsatellite markers individually genotyped, eight markers displayed distorted transmission with uncorrected P-value<0.05, ranked in this order: D6S2443 (6p21.32, HLA class II) (P corrected=0.01), D2S2201 (2p24), D19S552 (19q13), D3S3584 (3q21), D17S975 (17q11), D1S2627 (1p22), D6S273 (6p21.33, HLA class III) and D12S1051 (12q23). These non-HLA regions need further investigation as possible MS candidate gene regions in our population.

Urine-based testing for Chlamydia trachomatis using polymerase chain reaction, leucocyte esterase and urethral and cervical smears.

The performance of Roche polymerase chain reaction (PCR) Amplicor to detect Chlamydia trachomatis in first-voided urine specimens from 422 males and 456 females attending two clinics for sexually transmitted infections was evaluated in comparison with cultures of urethral and cervical specimens. At the same time, the ability of leucocyte esterase (LE) in first-voided urine and the presence of leucocytes in urethral and cervical smears to identify C. trachomatis-infected individuals based on PCR and culture was determined. The prevalence of C. trachomatis infection was 10.9% in men and 7.7% in women. Sensitivity, specificity, positive predictive value and negative predictive value of Amplicor was 93.5%, 99.7%, 97.7% and 99.2% in males and 91.4%, 99.5%, 94.1% and 99.3% in females. All Chlamydia-infected men were identified by means of a combination of urethritis (4 leucocytes in the urethral smear) and/or a positive LE test in urine, although the specificity was only 42.2%. In women, the combination of urethritis and/or cervicitis and/or a positive LE test identified 85.7% of Chlamydia-infected patients with a specificity of 38.2%. It is concluded that a combination of urethral and/or cervical smears and LE testing of urine can be used as a screening test to select patients, especially males, for specific C. trachomatis testing.

Updated results of the United Kingdom linkage-based genome screen in multiple sclerosis.

In 1996, we reported the results of a linkage genome screen based on 129 UK multiple sclerosis multiplex families, together with follow-up typing of interesting regions in a second set of families. We have now completed screening the remainder of the genome in this second set of United Kingdom families by typing 242 microsatellite markers. These data have been analysed together with those previously published, resulting in the largest currently available whole genome linkage dataset from a single population in multiple sclerosis. Four new regions of potential linkage (chromosomes 10p, 11p, 19p, 20p) not previously described were identified. In the combined analysis of all 226 families, a total of five regions of suggestive linkage are seen (chromosomes 1p, 6p, 14q, 17q, Xq), where only one would have been expected to occur by chance alone.

Applying the International Classification of Functioning, Disability and Health (ICF) to measure childhood disability.

The International Classification of Functioning, Disability and Health-ICF addresses the broad need for a common language and classification of functioning and disability. A parallel need is appropriate measures compatible with the content of the ICF to document the nature and impact of limitations of function, activities and participation. The interaction of developmental characteristics and disability among children represent special challenges for classification as well as measurement. Demographic trends emphasize the need for universal measures that encompass the components of the ICF and can be used in surveillance, screening and evaluation. This paper identifies issues related to application of the ICF to measure disability in childhood; reviews approaches and tools to assess childhood disability and identifies priorities for the development of measures of functioning and disability in children based on the ICF. The development of measures should be framed within a framework of children's rights and application of the biopsychosocial model to document profiles of functioning and disability of children.

An immunocytochemical analysis of torn rotator cuff tendon taken at the time of repair.

During rotator cuff repairs, it is recommended that the hypovascular tissue edge be resected. To investigate rotator cuff tendon histopathology, we performed immunohistochemistry on 8 surgical and 6 cadaveric specimens. Hoechst nuclear stain and standard hematoxylin-eosin were used for morphologic analysis. Antibody to human von Willebrand factor tagged with fluorescein isothiocyanate, conjugated, was used to visualize vascularity, and antibody to human procollagen type I tagged with Cy3 was used to visualize new procollagen synthesis. There were no significant differences in the vascularity of surgical specimens sectioned near the tear site (<2.5 mm from tear margin) and matched cadaveric controls. However, sections taken 2.5 to 5 mm away from the tear demonstrated more vessels than those taken from either control or surgical specimens within 2.5 mm of the tear (P <.001). There were no differences in nuclear distribution patterns or in procollagen production and distribution between surgical specimens from sites near the tear or away from the tear. On the basis of morphologic architecture, these data suggest that minimal debridement of tendon edges only is required to maximize healing of the rotator cuff tendon at the time of repair.

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis.

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.

Solid human embryonic spinal cord xenografts in acute and chronic spinal cord cavities: a morphological and functional study.

While therapeutic spinal cord grafting procedures are of interest in the chronic spinal cord injury stage, previous experimental grafting studies, including human spinal cord tissue, have mainly focused on the acute stage. Therefore, solid human embryonic spinal cord grafts were implanted in acute or chronic spinal cord aspiration cavities of immunodeficient rats to compare the morphological and locomotor outcome to that of lesion alone cases. Locomotor function was assessed using the Basso, Beattie, and Bresnahan open-field locomotor rating scale up to 6 months, while the morphological evaluation of graft survival, growth, and integration was performed at 6 weeks or 6 months after implantation. Graft survival was 94% in both lesion models, while graft growth was enhanced in the chronic compared to the acute cavity group. Human specific Thy-1 and neurofilament immunoreactive fibers were observed up to 7 mm into host white matter, while aminergic fibers were observed up to 1 mm into the grafts. Abundant calcitonin gene-related peptide immunoreactive fibers in the grafts in the absence both of immunoreactive cell bodies and colocalized human-specific neurofilament immunoreactivity, suggested host fiber ingrowth. At 6 months, the grafted cases presented less central canal deformation and lower glial fibrillary acidic protein immunoreactivity at the host cavity border compared to that of the nongrafted cases. The strong compensatory regain of locomotor function after unilateral spinal cord lesions was not affected by the human spinal cord grafts. In conclusion, solid human embryonic spinal cord tissue transplanted to a cavity in the adult injured spinal cord results in beneficial morphological effects in both the acute and chronic spinal cord lesion.

MHC antigen expression in human first trimester spinal cord with implications for clinical transplantation procedures.

We report human leukocyte antigen (HLA) class I expression in 5-17% and class II in 0-9% of first trimester human spinal cord cells. After 8 days in culture with gamma-interferon, >87% of the spinal cord cells expressed HLA class II. However, mixed cultures of adult human peripheral lymphocytes and immature human spinal cord cells, showed no induction of lymphocyte proliferation prior to or after gamma-interferon exposure in culture. In conclusion, we report non-immunogenic expression of HLA antigens in the human first trimester spinal cord.

An ultrafast time-resolved anisotropy study of bacteriochlorophyll a in pyridine.

The transient absorption anisotropy spectrum of bacteriochlorophyll a (BChl a) in pyridine was measured in the wavelength interval 550-850 nm, 1 ps after optical excitation with a 792-nm femtosecond light pulse. In the wavelength region of Q(y) absorption and stimulated emission (775-825 nm), the anisotropy was found to be close to the theoretically expected value (0.4) for a two-level system. In the wavelength region 650-750 nm, where the transient absorption signal is dominated by excited state absorption, the anisotropy is reduced to approximately 0.18. Anisotropy kinetics were measured at several wavelengths and found to be constant within the time window 0-5 ps, showing that no internal dynamics of the BChl a molecule change the anisotropy on the time scale of tens of picoseconds.

Ionotropic glutamate receptor expression in human spinal cord during first trimester development.

Quantitative receptor autoradiography and immunoblotting were used to study the expression and distribution of AMPA, kainate and NMDA receptors in first trimester human spinal cord obtained from elective abortions ranging from 4 to 11.5 weeks of gestational age. Spinal cord tissue sections were processed for receptor autoradiography with the ligands [3H]AMPA, [3H]kainate and [3H]MK-801 and the optical density was measured separately in a dorsal region (alar plate) and ventral region (basal plate) of the autoradiographs. Binding sites for all three ligands were demonstrated already at 4-5.5 weeks of gestation and increased continuously during the first trimester both in the dorsal and ventral regions. [3H]AMPA binding to both high- and low-affinity sites increased from undetectable levels to about 35 and 400 fmol/mg tissue, respectively, during this period. A temporal difference in the distribution of [3H]AMPA binding sites was observed. The early homogeneous pattern of [3H]AMPA binding in both alar and basal plates had changed to a heterogeneous pattern at 11 weeks of gestation with the highest density of [3H]AMPA binding sites in the superficial layers of the immature dorsal horn. [3H]kainate and [3H]MK-801 binding sites were densely and homogeneously distributed already at 4 weeks, and steadily increased six- and two-fold, respectively, to about 100 fmol/mg tissue at 11.5 weeks of gestation. Immunoreactive bands corresponding to the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D were demonstrated by immunoblotting at the earliest between 4.5 and 7 weeks and increasing concentrations were seen up to 11 weeks of gestation. These results suggest that AMPA, kainate and NMDA receptors are expressed in the human spinal cord early in embryogenesis.

Nerve growth factor-induced stimulation of dorsal root ganglion/spinal cord co-grafts in oculo: enhanced survival and growth of CGRP-immunoreactive sensory neurons.

Intraocular co-grafts of rat fetal spinal cord and dorsal root ganglia were used to examine the enhanced survival, growth, and differentiation of sensory neurons by nerve growth factor. E14 lumbar spinal segments were implanted into the anterior eye chamber of capsaicin-pretreated rats. Two weeks later, an E14 dorsal root ganglion was implanted beside the spinal cord graft. Nerve growth factor or vehicle was injected weekly for 4 weeks into the anterior eye chamber. Co-grafts were examined weekly and, at 6 weeks, processed for calcitonin gene-related peptide (CGRP) immunofluorescence. No differences in overall size were determined for the grafts. Co-grafts treated with nerve growth factor contained many more CGRP neurons (19.4 cells/20 microm) that were significantly larger (mean 764 microm2) than neurons from control co-grafts (8.6 cells/20 microm; mean 373 microm2). In co-grafts treated with nerve growth factor, CGRP-immunoreactive fibers were extensive in the dorsal root ganglion, adjacent iris, and spinal cord compared to control co-grafts. A few CGRP-positive motoneurons were observed in the spinal cord, but no differences in number or size of motoneurons were found. The current report demonstrates that spinal cord and dorsal root ganglia can be co-grafted in oculo for long periods of time. Many dorsal root ganglion neurons survive and send peripheral processes into the iris and central processes into the spinal cord under the influence of exogenous nerve growth factor. The intraocular graft paradigm can be of use to further examine the role of neurotrophic factors in regulating or modulating dorsal root ganglion and spinal cord neurons.

Human embryonic spinal cord grafts in adult rat spinal cord cavities: survival, growth, and interactions with the host.

The ability of solid pieces of transplanted human embryonic spinal cord to survive, grow, and integrate with adult rat host spinal cord tissue was investigated. Unilateral cavities were surgically created at vertebral level T12-T13 in 10 athymic nude rats and 5 regular Sprague-Dawley rats. Seven of the athymic rats acutely received a human spinal cord graft, while the remaining 8 rats served as controls, with cavities alone. After 6 months the morphological outcome was evaluated with cresyl violet and with immunohistochemistry using antibodies toward human-specific neurofilament (hNF), human-specific Thy-1 (Thy-1), neurofilament, glial fibrillary acidic protein, serotonin (5-HT), and tyrosine hydroxylase (TH). The in situ morphology of the human embryonic spinal cord was also investigated and compared with grafts that were six months older. Solid human embryonic spinal cord grafts showed a 100% survival rate, grew to fill the volume of the cavity in a noninvasive manner, and expressed human specific antigens 6 months postgrafting. Thy-1 immunoreactivity (IR) was demonstrated up to 8 mm rostral to the graft suggestive of graft-derived fiber outgrowth. hNF-IR fibers and 5-HT- and TH-IR fibers traversed the graft-host border for a few hundred micrometers, respectively. Finally, our findings suggest that grafted solid pieces of human embryonic spinal cord minimize cystic deformations seen in the adult rat spinal cord with a unilateral cavity.

Obliteration of a posttraumatic spinal cord cyst with solid human embryonic spinal cord grafts: first clinical attempt.

Cystic lesions of the spinal cord (syringomyelia) may occur after spinal cord injury. Posttraumatic syringomyelia may result in a myelopathy causing symptoms of sensory and motor loss, as well as worsening spasticity, pain, hyperhidrosis, and autonomic dysreflexia. Shunting of the cyst cavity along with untethering of the scarred spinal cord is widely accepted as the treatment of choice. However, the long-term stabilization of the progressive myelopathy caused by a posttraumatic cyst is suboptimal because of arachnoidal rescarring, shunt tube blockage, and cyst reexpansion. A new neurosurgical strategy to overcome the complication of cyst reexpansion was designed. Experimental studies have shown the successful use of embryonic spinal cord grafts, including human grafts, to obliterate induced spinal cord cavities in rats. The authors report the first use of solid human embryonic spinal cord grafts to successfully obliterate 6 cm of a large cyst cavity in a patient becoming myelopathic from a posttraumatic cyst. The grafts are well visualized by MRI to the 7-month postoperative follow-up and cyst obliteration is seen in the region where the grafts were placed.

First trimester development of the human nigrostriatal dopamine system.

The aim of the present study was to characterize the morphological and neurochemical differentiation of mesencephalic dopaminergic neurons in human embryos, derived from elective first trimester abortions. Embryonic brain tissue was taken for analysis of tyrosine hydroxylase (TH) by immunohistochemistry and Western blot, and for analysis of endogenous dopamine (A) content using HPLC-ED. TH expression was first detected at 3.5 weeks of gestational age (Carnegie stage 11) by immunohistochemical staining of the primordial sympathetic trunk along both sides of the neural tube. In sagittal sections of the intact 4.5-week-old embryo, a small, distinct population of rounded, densely packed TH-immunoreactive perikarya with short primary processes was seen in the midbrain. During the latter half of the first trimester, the number of TH-stained cells as well as the length and number of axonal processes projecting toward and into the developing neostriatum increased rapidly. At the end of the first trimester, varicose fibers could be detected in the striatal anlage. In order to verify that TH was the antigen recognized by the antibodies used for immunohistochemistry on human tissue specimens, mesencephalic tissue of 5-10 weeks gestation was analyzed by Western blot technique. A single, homogeneous band with the apparent molecular weight of approximately 60 kDa was clearly detected at 5 weeks of age. The amount of TH/mg total protein increased at least 10-fold between 5-10 weeks of gestation. For comparison, the mesencephalon and the forebrain/basal ganglia were analyzed for endogenous DA content using HPLC-ED. DA was first detected at 5.5 weeks of gestational age in both mid- and forebrain, and DA levels were found to increase exponentially from 7 to 7.5 weeks of age, reaching 4-5.5 ng DA/mesencephalon and 50-75 ng DA/g caudate nucleus-putamen anlage at the end of the first trimester. Together, morphological and biochemical data presented here constitute evidence for a very early appearance, migration, and differentiation as well as functional development of human mesencephalic dopaminergic neurons and their projections into target areas during the first trimester.

Energy migration in the light-harvesting antenna of the photosynthetic bacterium Rhodospirillum rubrum studied by time-resolved excitation annihilation at 77 K.

The intensity dependence of picosecond kinetics in the light-harvesting antenna of the photosynthetic bacterium Rhodospirillum rubrum is studied at 77 K. By changing either the average excitation intensity or the pulse intensity we have been able to discriminate singlet-singlet and singlet-triplet annihilation. It is shown that the kinetics of both annihilation types are well characterized by the concept of percolative excitation dynamics leading to the time-dependent annihilation rates. The time dependence of these two types of annihilation rates is qualitatively different, whereas the dependencies can be related through the same adjustable parameter-a spectral dimension of fractal-like structures. The theoretical dependencies give a good fit to the experimental kinetics if the spectral dimension is equal to 1.5 and the overall singlet-singlet annihilation rate is close to the value obtained at room temperature. The percolative transfer is a consequence of spectral inhomogeneous broadening. The effect is more pronounced at lower temperatures because of the narrowing of homogeneous spectra.