Care of Late-Stage Parkinsonism: Resource Utilization of the Disease in Five European Countries.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. OBJECTIVE: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. METHODS: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. RESULTS: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. CONCLUSION: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

BACKGROUND: Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. METHODS: GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. RESULTS: Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. CONCLUSIONS: Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.

The Use of IL-17 and IL-23 Inhibitors in Swedish Clinical Practice: A Register-Based Analysis.

BACKGROUND: Interleukin (IL) inhibitors have made completely cleared skin achievable for many patients with moderate to severe psoriasis in clinical trial settings. Few observational studies assess treatment response in accordance with treatment goals in guidelines. OBJECTIVES: The aim of the study was to analyze the treatment response of IL-17/IL-23 inhibitors in clinical practice and the proportions of patients that reach the treatment target of the Psoriasis Area and Severity Index (PASI) < 3 and the Dermatology Life Quality Index (DLQI) ≤5. METHODS: A longitudinal, observational study based on the Swedish National Registry for Systemic Treatment of Psoriasis, PsoReg. Patients using IL-17/IL-23 inhibitors with assessments of PASI, DLQI, and EQ-5D before (maximum 6 months) and after (3-12 months) initiation of IL-17/IL-23 were included. RESULTS: In total, 333 patients using IL-17/IL-23 inhibitors were included. Eighty percent (n = 266) received IL-17 inhibitors, and 20% (n = 67) received IL-23 inhibitors. Sixty-six percent of patients reached both PASI <3 and DLQI ≤5, 23% reached one target, and 11% reached none. The mean (SD) PASI, DLQI, and EQ-5D improvements were 6.75 (6.99), 7.14 (7.97), and 0.126 (0.296), respectively. There was no statistically significant difference in outcomes between IL-17 and IL-23 inhibitor treatment groups. CONCLUSIONS: IL-17/IL-23 inhibitors are effective in clinical practice, but there is still an unmet therapeutic need in moderate to severe psoriasis.

Economic Burden of Palmoplantar Pustulosis in Sweden: A Population-based Register Study.

The aim of this study was to estimate the economic burden of palmoplantar pustulosis, a chronic relapsing skin condition commonly occurring in combination with psoriasis vulgaris. Using data from the Swedish National Patient Register and Swedish Prescribed Drug Register for 2015, the study estimated all-cause and palmoplantar pustulosis-specific healthcare resource use (inpatient stays, physician visits and drug use) for 14,715 patients with palmoplantar pustulosis, and compared these both with matched controls from the general population and with patients with psoriasis vulgaris (without palmoplantar pustulosis). Mean annual direct costs for a patient with palmoplantar pustulosis was higher compared with costs for the general population (3,000 vs 1,700 Euro, p < 0.001). Compared with psoriasis vulgaris, more patients with palmoplantar pustulosis had inpatient stays, but fewer had physician visits and psoriasis-related drugs; the overall costs were similar. Only a small fraction of the costs of physician visits and inpatient stays for patients with palmoplantar pustulosis were attributable to specific palmoplantar pustulosis problems, indicating a clear comorbidity burden in palmoplantar pustulosis.

Prolonged Sick Leave Before and After Diagnosis of Generalized Pustular Psoriasis: A Swedish Population-based Register Study.

The aim of this study was to analyse sick leave in generalized pustular psoriasis, the most severe form of pustular psoriasis. Prolonged sick leave of >14 days was analysed for 502 patients with generalized pustular psoriasis compared with controls with psoriasis vulgaris and matched controls from the general population. Using data from the Swedish National Patient Register, and the Longitudinal integrated database for health insurance and labour market studies, the study estimated the mean number of sick leave days in the year of first diagnosis of generalized pustular psoriasis (index year) and for 2 years before and after the index year. Patients with generalized pustular psoriasis were on sick leave to a larger extent than both control populations for all study years. The number of sick leave days peaked in the index year and then reduced. Compared with the control populations, sick leave in generalized pustular psoriasis was already higher prior to diagnosis, indicating delayed diagnosis and/or a comorbidity burden.

Prevalence and incidence of generalized pustular psoriasis in Sweden: a population-based register study.

BACKGROUND: Generalized pustular psoriasis (GPP) is a severe form of pustular psoriasis with generalized eruption of sterile pustules, often along with systemic symptoms. There is a scarcity of population-based estimates of GPP prevalence and incidence. OBJECTIVES: To estimate (i) the prevalence and incidence of GPP in the Swedish general population and (ii) the prevalence of psoriasis vulgaris within the GPP population. METHODS: We identified cases (2004-2015) with one ICD-10 diagnostic code (base case) for GPP within the Swedish National Patient Register, which covers inpatient and outpatient secondary care. Cases were linked to the Swedish Total Population Register, and point prevalence was estimated as on 31 December 2015. In two alternative analyses we changed case definitions to: (i) requiring two visits (strict case 1) and (ii) requiring two visits of which one was within dermatology/internal medicine (strict case 2). RESULTS: The base case point prevalence of GPP was estimated at 9.1 per 100 000 (women, 11.2; men, 7.0) and the annual prevalence in 2015 was estimated at 1.53 per 100 000. Among the GPP population, 43% also had a psoriasis vulgaris code. The incidence of GPP in 2015 was estimated at 0.82 per 100 000 (women, 0.93; men, 0.74). The criteria used had an impact on prevalence and incidence estimates: prevalence strict case 1 gave 3.8 per 100 000 and incidence strict case 1 gave 0.42 per 100 000. CONCLUSIONS: Results indicate that the estimated GPP population in Sweden is within the range of previous published estimates. However, estimates were sensitive to the GPP case criteria used. The findings enhance demands for studies using validated diagnostic algorithms.

Quality of life and resource utilization-Swedish data from the Care of Late-Stage Parkinsonism (CLaSP) study.

BACKGROUND: Few studies have investigated the health-related quality of life (HRQoL), resource use and costs in patients with late-stage Parkinson's disease (PD), and data from the Swedish setting are scarce. OBJECTIVES: First, we analyse the HRQoL in late-stage PD in Sweden. Second, we analyse the resource use and costs per severity level. Third, we analyse the relationship between costs and physician- and patient reported-outcome measures. MATERIALS AND METHODS: The study was based on Swedish data from the Care of Late-Stage Parkinsonism (CLaSP) study. The costs of healthcare contacts, drugs, formal and informal care, and productivity loss were collected over three months. Assessments at baseline were used for outcomes (EQ-5D, Hoehn and Yahr (H&Y), Schwab and England Scale, Unified Parkinson's Disease Rating Scale subscales (UPDRS) and Non-Motor Symptoms Scale (NMSS)). Costs were estimated in € 2016. RESULTS: In total, 106 patients were included. The mean EQ-5D score in the total group was 0.24 (±0.33). The mean total cost excluding informal care per patient in the three-month period was approximately €14,097 (BCa 95% CI €12,007 and €16,039). Professional care accounted for the largest share (75 percent) of the total costs. The EQ-5D, H&Y, Schwab and England Scale, and NMSS were statistically significant predicting factors for total costs. CONCLUSION: Patients with late-stage PD are a vulnerable patient group that is costly to society and the impairment in patients' HRQoL is immense. Thus, healthcare decision-makers should optimize the organization and provision of healthcare for these patients.

Parkinson's disease in Sweden-resource use and costs by severity.

OBJECTIVES: To estimate resource use and costs, including direct and indirect costs, in relation to levels of severity in individuals with Parkinson's disease (PD) in a Swedish setting. MATERIALS AND METHODS: Patients with idiopathic PD registered in the National Parkinson's Disease Patient Registry (PARKreg), with registrations of Hoehn and Yahr (H&Y) and "off time" in the Skåne Region, were included. Annual costs of healthcare contacts, drugs, formal and informal care, and productivity loss associated with PD were estimated using data from PARKreg linked with regional and national healthcare registers between 2013 and 2019. RESULTS: In total, 960 patients and 1324 observations (patient-years) were included. Total average cost per patient-year was SEK 168,982 (EUR 15,958) and ranged from SEK 62,404 (EUR 5893) for H&Y stage I to SEK 1,056,324 (EUR 99,755) in H&Y stage V. The dominating part of total costs for early stages were indirect costs accounting for 50-60% while formal care made up for 55% and 81% of total costs in H&Y IV and V, respectively. Total mean costs for formal care, informal care, and productivity loss also increased with increasing off-time. CONCLUSION: Advanced and late stages of PD are associated with significant societal costs as patients in those stages often require resource-intensive and costly formal care. Thus, there are potential savings to be made, by optimizing the pharmacological and surgical symptomatic treatment of patients with advanced disease.

Swedish guidelines for device-aided therapies in Parkinson's disease -Economic evaluation and implementation.

OBJECTIVES: The National Board of Health and Welfare in Sweden published the national guidelines for Parkinson's Disease 2016. The aim of this study was to summarize this evidence review and development of the guidelines, focusing on the economic evaluation of device-aided therapies (deep brain stimulation, pump-based infusion of levodopa-carbidopa intestinal gel or apomorphine) for Parkinson's disease, and the rate of implementation after 3 years in Sweden. MATERIAL AND METHODS: The evidence review underlying the guidelines-including systematic literature searches of clinical and economic evidence, model-based economic evaluation, and formal analysis and guideline development-was examined, condensed, and translated. The impact of the guidelines was assessed with treatment use statistics from 2009 to 2019. RESULTS: All device-aided therapies were assigned high priority. Based on a relatively low proportion of device-aided therapies (30%) in Parkinson's disease, a 5-year increase of 500 patients was recommended. This was estimated to reduce total costs by SEK 14 million (€1.7 million). Follow-up data found an increase of 217 patients between 2017 and 2019, following the same trend as before the guidelines. CONCLUSION: Three years after the guidelines were published, the use of device-aided therapies has increased in Sweden, albeit not in pace with recommendations. One reason for slow implementation may be poor incentivization related to budget silos in which the costs for device-aided therapies are borne by the regions but the cost offsets (eg, reduced need for home care) are reaped by local stakeholders.

Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model.

Uncontrolled activation of transforming growth factor beta (TGF-ß) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-ß family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-ß family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.

N-glycosylation proteome enrichment analysis in kidney reveals differences between diabetic mouse models.

BACKGROUND: Diabetic nephropathy (DN) is a late complication in both type 1 diabetes mellitus (T1DM) and T2DM. Already at an early stage of DN morphological changes occur at the cell surface and in the extracellular matrix where the majority of the proteins carry N-linked glycosylations. These glycosylated proteins are highly important in cell adhesion and cell-matrix processes but not much is known about how they change in DN or whether the distinct etiology of T1DM and T2DM could have an effect on their abundances. METHOD: We enriched for the N-glycosylated kidney proteome in db/db mice dosed with insulin or vehicle, in streptozotocin-induced (STZ) diabetic mice and healthy control mice dosed with vehicle. Glycopeptides were analyzed with label-free shotgun mass spectrometry and differential protein abundances identified in both mouse models were compared using multivariate analyses. RESULTS: The majority of the N-glycosylated proteins were similarly regulated in both mouse models. However, distinct differences between the two mouse models were for example seen for integrin-ß1, a protein expressed mainly in the glomeruli which abundance was increased in the STZ diabetic mice while decreased in the db/db mice and for the sodium/glucose cotransporter-1, mainly expressed in the proximal tubules which abundance was increased in the db/db mice but decreased in the STZ diabetic mice. Insulin had an effect on the level of both glomerular and tubular proteins in the db/db mice. It decreased the abundance of G-protein coupled receptor-116 and of tyrosine-protein phosphatase non-receptor type substrate-1 away from the level in the healthy control mice. CONCLUSIONS: Our finding of differences in the N-glycosylation protein profiles in the db/db and STZ mouse models suggest that the etiology of DN could give rise to variations in the cell adhesion and cell-matrix composition in T1DM and T2DM. Thus, N-glycosylated protein differences could be a clue to dissimilarities in T1DM and T2DM at later stages of DN. Furthermore, we observed insulin specific regulation of N-glycosylated proteins both in the direction of and away from the abundances in healthy control mice.

Evaluation of Resource Utilization and Treatment Patterns in Patients with Actinic Keratosis in the United States.

OBJECTIVE: To compare health care resource utilization and treatment patterns between patients with actinic keratosis (AK) treated with ingenol mebutate gel (IngMeb) and those treated with other field-directed AK therapies. METHODS: A retrospective, propensity-score-matched, cohort study compared refill/repeat and adding-on/switching patterns and outpatient visits and prescriptions (health care resource utilization) over 6 months in patients receiving IngMeb versus those receiving imiquimod, 5-fluorouracil, diclofenac sodium, and methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT). RESULTS: The final sample analyzed included four matched treatment cohort pairs (IngMeb and comparator; n = 790-971 per treatment arm). Refill rates were similar except for imiquimod (15% vs. 9% for imiquimod and IngMeb, respectively; P < 0.05). MAL/ALA-PDT treatment repetition rates were higher than IngMeb refill rates (20% vs. 10%; P < 0.05). Topical agent add-on/switch rates were comparable. PDT had higher switch rates than did IngMeb (5% vs. 2%; P < 0.05). The IngMeb cohort had a significantly lower proportion of patients with at least one AK-related outpatient visit during the 6-month follow-up than did any other cohort: versus imiquimod (50% vs. 66%; P < 0.0001), versus 5-fluorouracil (50% vs. 69%; P < 0.0001), versus diclofenac sodium (51% vs. 56%; P = 0.034), and versus MAL/ALA-PDT (50% vs. 100%; P < 0.0001). There were significantly fewer AK-related prescriptions among patients receiving IngMeb than among patients in other cohorts. CONCLUSIONS: Results based on the first 6 months after treatment initiation suggested that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with higher refill rates, and PDT, which was associated with significantly more frequent treatment sessions and higher switching rates. IngMeb was also associated with significantly fewer outpatient visits than were other field-directed therapies.

Pericytes regulate the blood-brain barrier.

The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.

Resource use in patients with psoriasis after the introduction of biologics in Sweden.

The introduction of biologics has changed treatment patterns as well as costs in patients with psoriasis. This study was performed to estimate direct and indirect costs of the psoriasis population in Sweden, and to analyse changes in costs between 2006 and 2009. The study population was identified in national registers. Direct costs included health care visits with primary psoriasis diagnoses in specialist care and drugs relevant for treating psoriasis. Productivity loss, including costs of long-term sick leave and disability pension, was estimated as the difference between psoriasis patients and matched controls from the general population. Total direct cost increased from SEK 348 million (~ €39) in 2006 to SEK 459 million (~ €51) in 2009, whereas the total productivity loss decreased from SEK 1,646 (~ €183) to 1,618 million (~ €180) between 2006 and 2009. Although direct costs, especially for biologic agents, have increased for patients with psoriasis over time, this study indicates that costs related to productivity loss are still more substantial.

Health-related quality of life in patients with generalized pustular psoriasis - a Swedish register study.

BACKGROUND: Real-world data on health-related quality of life (HRQoL) in generalized pustular psoriasis (GPP) are scarce and studies have been restricted in terms of instruments used for assessments. OBJECTIVE: To assess generic and dermatology-specific HRQoL of patients with GPP compared with patients with plaque psoriasis using real-world data from the Swedish National Register for Systemic Treatment of Psoriasis. METHODS: Cross-sectional data from 2006 to 2021 including 7041 individuals with plaque psoriasis without GPP and 80 patients with GPP, of which 19% also had plaque psoriasis. Total scores for the EuroQol-5 Dimensions (EQ-5D) and Dermatology Life Quality Index (DLQI), as well as degree of severity within the instruments' dimensions/questions, were compared between patient groups. RESULTS: EQ-5D scores were significantly (p < .01) lower (worse) in patients with GPP (mean [standard deviation (SD)] 0.613 [0.346]) vs. patients with plaque psoriasis (mean [SD] 0.715 [0.274]), indicating lower generic HRQoL of patients with GPP. Significantly (p < .01) higher (worse) total DLQI scores were observed for patients with GPP (mean [SD] 10.6 [8.9]) compared with patients with plaque psoriasis (mean [SD] 7.7 [7.1]), with proportionally more patients with GPP having severe (20% vs. 16%) and very severe (17% vs. 8%) problems. The worsened scores for GPP vs. plaque psoriasis were consistent across EQ-5D dimensions and DLQI questions. CONCLUSIONS: Individuals with GPP have a considerable impairment in both generic and dermatology-specific HRQoL. The HRQoL was significantly worse in individuals with GPP compared to individuals with plaque psoriasis. The significant HRQoL impairment of GPP shows the potential value of better healthcare interventions for this multisystem disease.

The study assessed health-related quality of life (HRQoL) in patients with generalized pustular psoriasis (GPP) compared to patients with plaque psoriasis using real-world data from the Swedish National Register for Systemic Treatment of Psoriasis.The results showed significantly worse HRQoL scores by two different HRQoL instruments (EuroQol-5 Dimensions [EQ-5D] and Dermatology Life Quality Index [DLQI]) in patients with GPP compared to patients with plaque psoriasis.The study indicates that individuals with GPP have a considerable impairment in both generic and dermatology-specific HRQoL.

Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients.

OBJECTIVE: The metabolic benefits of GLP-1 receptor (GLP-1R) agonists on glycemic and weight control are well established as therapy for type 2 diabetes and obesity. Glucagon's ability to increase energy expenditure is well described, and the combination of these mechanisms-of-actions has the potential to further lower hepatic steatosis in metabolic disorders and could therefore be attractive for the treatment for non-alcoholic steatohepatitis (NASH). Here, we have investigated the effects of a dual GLP-1/glucagon receptor agonist NN1177 on hepatic steatosis, fibrosis, and inflammation in a preclinical mouse model of NASH. Having observed strong effects on body weight loss in a pilot study with NN1177, we hypothesized that direct engagement of the hepatic glucagon receptor (GCGR) would result in a superior effect on steatosis and other liver related parameters as compared to the GLP-1R agonist semaglutide at equal body weight. METHODS: Male C57Bl/6 mice were fed a diet high in trans-fat, fructose, and cholesterol (Diet-Induced Obese (DIO)-NASH) for 36 weeks. Following randomization based on the degree of fibrosis at baseline, mice were treated once daily with subcutaneous administration of a vehicle or three different doses of NN1177 or semaglutide for 8 weeks. Hepatic steatosis, inflammation and fibrosis were assessed by immunohistochemistry and morphometric analyses. Plasma levels of lipids and liver enzymes were determined, and hepatic gene expression was analyzed by RNA sequencing. RESULTS: NN1177 dose-dependently reduced body weight up to 22% compared to vehicle treatment. Plasma levels of ALT, a measure of liver injury, were reduced in all treatment groups with body weight loss. The dual agonist reduced hepatic steatosis to a greater extent than semaglutide at equal body weight loss, as demonstrated by three independent methods. Both the co-agonist and semaglutide significantly decreased histological markers of inflammation such as CD11b and Galectin-3, in addition to markers of hepatic stellate activation (αSMA) and fibrosis (Collagen I). Interestingly, the maximal beneficial effects on above mentioned clinically relevant endpoints of NN1177 treatment on hepatic health appear to be achieved with the middle dose tested. Administering the highest dose resulted in a further reduction of liver fat and accompanied by a massive induction in genes involved in oxidative phosphorylation and resulted in exaggerated body weight loss and a downregulation of a module of co-expressed genes involved in steroid hormone biology, bile secretion, and retinol and linoleic acid metabolism that are also downregulated due to NASH itself. CONCLUSIONS: These results indicate that, in a setting of overnutrition, the liver health benefits of activating the fasting-related metabolic pathways controlled by the glucagon receptor displays a bell-shaped curve. This observation is of interest to the scientific community, due to the high number of ongoing clinical trials attempting to leverage the positive effects of glucagon biology to improve metabolic health.

A meta-analysis of expression signatures in glomerular disease.

Glomerular diseases represent major diagnostic and therapeutic challenges with classification of these diseases largely relying on clinical and histological findings. Elucidation of molecular mechanisms of progressive glomerular disease could facilitate quicker development. High-throughput expression profiling reveals all genes and proteins expressed in tissue and cell samples. These methods are very appropriate for glomerular disease as pure glomeruli can be obtained from kidney biopsies. To date, proteome profiling data are only available for normal glomeruli, but more robust transcriptome methods have been applied to many mouse model and a few human glomerular diseases. Here, we have carried out a meta-analysis of currently available glomerular expression data in normal and diseased glomeruli from mice, rats, and humans using a standardized protocol. The results suggest a potential for glomerular transcriptomics in identifying pathogenic pathways, disease monitoring, and the feasibility to use animal models to study human glomerular disease. We also found that currently there are no specific consensus biomarkers or pathways among different disease data sets, indicating there are likely disease-specific mechanisms and expression profiles. Thus, further transcriptomics and proteomics analysis, especially that of dynamic changes in the diseases, may lead to novel diagnostics tools and specific pharmacologic therapies.