Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia.

BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X­ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T­score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.

Resistance training-induced improvement in physical function is not associated to changes in endocrine somatotropic activity in prefrail older adults.

CONTEXT: Resistance training improves muscle function in prefrail and frail elderly. The role of the somatotropic axis in this physiologic process remains unclear. Insulin-like growth factor I (IGF-I) and its associated proteins Insulin-like growth factor binding protein 3 (IGFBP3) and acid labile subunit (ALS) build a circulating ternary complex that mediates growth hormone (GH) effects on peripheral organs and can serve as a measure of endocrine somatotropic activity. OBJECTIVE: The aim of this study was to assess the association between resistance training-induced changes in physical performance and basal levels of IGF-I, IGFBP-3 and ALS in prefrail older adults. METHODS: 69 prefrail community-dwelling older adults, aged 65 to 94 years, were randomly assigned to a 12-week period of strength or power training or to a control group. The study was registered at clinicaltrials.gov as NCT00783159. Serum concentrations of IGF-I, IGFBP-3 and ALS were measured at rest before and after the intervention. Hormonal differences were examined in relation to changes in physical performance assessed by the Short Physical Performance Battery (SPPB). RESULTS: While resistance training led to significant improvements in SPPB score it did not induce significant differences in somatotropic hormone concentrations. Pre- and post-intervention changes in IGF-I, IGFBP-3, ALS or IGF/IGFBP-3 molar ratio were not related to the intervention mode, even after adjustment for age, sex, nutritional status, as well as SPPB and hormone concentrations at baseline. CONCLUSION: Training-induced improvements in physical performance in prefrail older adults were not associated with significant changes in endocrine somatotropic activity.

Identification of early neurodegenerative pathways in progressive multiple sclerosis.

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

Peripheral Quantitative Computed Tomography Derived Muscle Density Is Associated With Physical Performance in Older Adults.

PURPOSE: The assessment of body composition is an integral part in diagnosing sarcopenia. The purpose of this study was to determine the relationships between peripheral quantitative computed tomography (pQCT)-derived measures of body composition and measures of physical performance in older adults. METHODS: Muscle density, muscle area, and fat area of 168 patients aged 65 years and older (76.3±6.5) were measured with pQCT at the distal forearm additionally to clinical assessment consisting of medical history, physical examination and physical assessment including hand grip strength, gait speed and chair rise tests. Regression analyses assessed associations between patients' physical performance and pQCT derived data. RESULTS: Among the three pQCT parameters, especially muscle density was significantly correlated with all of the three measures of physical performance even after adjusting for sex, age, BMI, vitamin D serum level and the level of physical activity. The same analysis for muscle area achieved significance level only for handgrip strength but not for gait speed nor for chair rise time. Fat area was significantly correlated only with gait speed after adjusting for sex and age. The association of muscle density with physical performance held up in an additional subanalysis stratified by body mass index. CONCLUSION: Muscle density, a proxy for muscle fat infiltration, seems to be better than muscle area or fat area at assessing muscle quality and physical performance in older adults. This association seems to be independent of the body mass index.

[Diagnostic and therapeutic approach to sarcopenia]. / Diagnostisches und therapeutisches Vorgehen bei Sarkopenie.

Sarcopenia describes a generalized loss of muscle power, mass and function. It is marked by an impaired quality of life and an increased mortality rate. The SARC­F questionnaire was developed as a screening tool to identify patients at risk of impairment in primary care. It addresses five functional areas of physical activity in daily life. In case of a relevant impairment this is to be followed by measurement of hand grip strength using a dynamometer and/or of leg muscle strength by the chair rising test. Patients with pathological results should undergo a measurement of the skeletal muscle index, e.g. by Dual-energy X­ray Absorptiometry. If this lies below the gender-specific threshold, the diagnostic criteria for sarcopenia are met. Cases with normal lean muscle mass are coined as probable sarcopenia. In both cases, causes must be clarified and treatment should be initiated. To differentiate between acute and chronic sarcopenia it is necessary to assess disease progress after a certain period of time.

Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). METHODS: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). FINDINGS: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. CONCLUSIONS: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. FUNDING: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome.

The spatial RNA integrity number assay for in situ evaluation of transcriptome quality.

The RNA integrity number (RIN) is a frequently used quality metric to assess the completeness of rRNA, as a proxy for the corresponding mRNA in a tissue. Current methods operate at bulk resolution and provide a single average estimate for the whole sample. Spatial transcriptomics technologies have emerged and shown their value by placing gene expression into a tissue context, resulting in transcriptional information from all tissue regions. Thus, the ability to estimate RNA quality in situ has become of utmost importance to overcome the limitation with a bulk rRNA measurement. Here we show a new tool, the spatial RNA integrity number (sRIN) assay, to assess the rRNA completeness in a tissue wide manner at cellular resolution. We demonstrate the use of sRIN to identify spatial variation in tissue quality prior to more comprehensive spatial transcriptomics workflows.

ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.

IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion.

Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.