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Retinitis pigmentosa (RP) is an inherited disorder that results in vision impairment but general and mutation-independent therapeutic strategies are not available. However, it is widely regarded that the cGMP system, including cGMP and its interactor cGMP-dependent protein kinase (PKG), acts as a crucial effector during retinal degeneration. We have previously identified a list of cGMP-PKG-dependent genes in the context of RP, and in this study, we further validated one of these, namely pyruvate kinase 2 (PKM2), and investigated the potential role of PKM2 for the photoreceptors’ well-being during RP. With the aid of organotypic retinal explant cultures, we pharmacologically manipulated the PKM2 activities in two different RP mouse models (rd2 and rd10) via the addition of TEPP-46 (a PKM2 activator) and found that activation of PKM2 alleviates the progress of photoreceptor death in the rd10 mouse model. We also noted that the expression of both PKM2 and one of its targets, glucose transporter-1 (Glut1), showed alterations depending on the degeneration state. The observations provide supportive evidence that PKM2 may serve as a novel potential molecular target in RP.

Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

The disease retinitis pigmentosa (RP) leads to photoreceptor degeneration by a yet undefined mechanism(s). In several RP mouse models (i.e., rd mice), a high cyclic GMP (cGMP) level within photoreceptors is detected, suggesting that cGMP plays a role in degeneration. The rap guanine exchange factor 4 (EPAC2) is activated by cyclic AMP (cAMP) and is an accepted cGMP-interacting protein. It is unclear whether and how cGMP interacts with EPAC2 in degenerating photoreceptors; we therefore investigated EPAC2 expression and interactions with cGMP and cAMP in retinas of the rd1 and rd10 models for retinal degeneration. EPAC2 expression in the photoreceptor layer increased significantly during rd1 and rd10 degeneration, and an increase in EPAC2 interactions with cGMP but not cAMP in the rd1 was also seen via a proximity ligation assay on histological sections. Retinal explant cultures revealed that pharmacological inhibition of the EPAC2 activity reduced the photoreceptor layer thickness in the rd10 retina, suggesting that EPAC2 inhibition promotes degeneration. Taken together, our results support the hypothesis that high degeneration-related cGMP leads to increased EPAC2 and cGMP interactions, inhibiting EPAC2. By inference, EPAC2 could have neuroprotective capacities that may be exploited in the future.

Cyclin dependent kinase 1 (CDK1) has long been known to drive the cell cycle and to regulate the division and differentiation of cells. Apart from its role in mitosis regulation, it also exerts multiple functions as a protein kinase, including engagement in cell death, possibly via a cell cycle-independent mechanism. The latter is suggested, since CDK1 re-expression can be found in non-dividing and terminally differentiated neurons in several neurodegeneration models. However, the details of if and how CDK1 might be involved in the neurodegenerative condition, retinitis pigmentosa (RP), which displays progressive vision loss, are unclear. In the present study, we investigated CDK1 in degenerating RP photoreceptors of the rd1 RP model, including whether there is a link between this kinase and the cGMP-PKG system, which is regarded as a disease driver. With experiments performed using either in vivo retinal tissue or in vitro material, via organotypic retinal explants, our results showed that CDK1 appears in the photoreceptors at a late stage of their degeneration, and in such a position, it may be associated with the cGMP-PKG network.

ObjectiveTo evaluate which factors are the most strongly related to self-perceived health among older men and describe the shape of the association between the related factors and self-perceived health using machine learning.Design and settingThis is a cross-sectional study within the population-based VAScular and Chronic Obstructive Lung disease study (VASCOL) conducted in southern Sweden in 2019.ParticipantsA total of 475 older men aged 73 years from the VASCOL dataset.MeasuresSelf-perceived health was measured using the first item of the Short Form 12. An extreme gradient-boosting model was trained to classify self-perceived health as better (rated: excellent or very good) or worse (rated: fair or poor) using self-reported data on 19 prevalent physician-diagnosed health conditions, intensity of 9 symptoms and 9 demographic and lifestyle factors. Importance of factors was measured in SHapley Additive exPlanations absolute mean and higher scores correspond to greater importance.ResultsThe most important factors for classifying self-perceived health were: pain (0.629), sleep quality (0.595), breathlessness (0.549), fatigue (0.542) and depression (0.526). Health conditions ranked well below symptoms and lifestyle variables. Low levels of symptoms, good sleep quality, regular exercise, alcohol consumption and a body mass index between 22 and 28 were associated with better self-perceived health.ConclusionsSymptoms are more strongly related to self-perceived health than health conditions, which suggests that the impacts of health conditions are mediated through symptoms, which could be important targets to improve self-perceived health. Machine learning offers a new way to assess composite constructs such as well-being or quality of life.

Background Women with endometriosis often experience gastrointestinal symptoms. Gonadotropin-releasing hormone (GnRH) analogs are used to treat endometriosis; however, some patients develop gastrointestinal dysmotility following this treatment. The aims of the present study were to investigate gastrointestinal symptoms among patients with endometriosis and to examine whether symptoms were associated with menstruation, localization of endometriosis lesions, or treatment with either opioids or GnRH analogs, and if hormonal treatment affected the symptoms. Methods All patients with diagnosed endometriosis at the Department of Gynecology were invited to participate in the study. Gastrointestinal symptoms were registered using the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS); socioeconomic and medical histories were compiled using a clinical data survey. Data were compared to a control group from the general population. Results A total of 109 patients and 65 controls were investigated. Compared to controls, patients with endometriosis experienced significantly aggravated abdominal pain ( P  = 0.001), constipation ( P  = 0.009), bloating and flatulence ( P  = 0.000), defecation urgency ( P  = 0.010), and sensation of incomplete evacuation ( P  = 0.050), with impaired psychological well-being ( P  = 0.005) and greater intestinal symptom influence on their daily lives ( P  = 0.001). The symptoms were not associated with menstruation or localization of endometriosis lesions, except increased nausea and vomiting ( P  = 0.010) in patients with bowel-associated lesions. Half of the patients were able to differentiate between abdominal pain from endometriosis and from the gastrointestinal tract. Patients using opioids experienced more severe symptoms than patients not using opioids, and patients with current or previous use of GnRH analogs had more severe abdominal pain than the other patients ( P  = 0.024). Initiation of either combined oral contraceptives or progesterone for endometriosis had no effect on gastrointestinal symptoms when the patients were followed prospectively. Conclusions The majority of endometriosis patients experience more severe gastrointestinal symptoms than controls. A poor association between symptoms and lesion localization was found, indicating existing comorbidity between endometriosis and irritable bowel syndrome (IBS). Treatment with opioids or GnRH analogs is associated with aggravated gastrointestinal symptoms.

Photoreceptor cell death is the major hallmark of a group of human inherited retinal degenerations commonly referred to as retinitis pigmentosa (RP). Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Previous research work has focused on apoptosis, but recent evidence suggests that photoreceptor cell death may result primarily from non-apoptotic mechanisms independently of AP1 or p53 transcription factor activity, Bcl proteins, caspases, or cytochrome c release. This review briefly describes some animal models used for studies of retinal degeneration, with particular focus on the rd1 mouse. After outlining the major features of different cell death mechanisms in general, we then compare them with results obtained in retinal degeneration models, where photoreceptor cell death appears to be governed by, among other things, changes in cyclic nucleotide metabolism, downregulation of the transcription factor CREB, and excessive activation of calpain and PARP. Based on recent experimental evidence, we propose a putative non-apoptotic molecular pathway for photoreceptor cell death in the rd1 retina. The notion that inherited photoreceptor cell death is driven by non-apoptotic mechanisms may provide new ideas for future treatment of RP.

Inherited retinal degenerative diseases (IRDs) are a group of rare diseases that lead to a progressive loss of photoreceptor cells and, ultimately, blindness. The overactivation of cGMP-dependent protein kinase G (PKG), one of the key effectors of cGMP-signaling, was previously found to be involved in photoreceptor cell death and was studied in murine IRD models to elucidate the pathophysiology of retinal degeneration. However, PKG is a serine/threonine kinase (STK) with several hundred potential phosphorylation targets and, so far, little is known about the specificity of the target interaction and downstream effects of PKG activation. Here, we carried out both the kinome activity and phosphoproteomic profiling of organotypic retinal explant cultures derived from the rd10 mouse model for IRD. After treating the explants with the PKG inhibitor CN03, an overall decrease in peptide phosphorylation was observed, with the most significant decrease occurring in seven peptides, including those from the known PKG substrate cyclic-AMP-response-element-binding CREB, but also Ca2+/calmodulin-dependent kinase (CaMK) peptides and TOP2A. The phosphoproteomic data, in turn, revealed proteins with decreased phosphorylation, as well as proteins with increased phosphorylation. The integration of both datasets identified common biological networks altered by PKG inhibition, which included kinases predominantly from the so-called AGC and CaMK families of kinases (e.g., PKG1, PKG2, PKA, CaMKs, RSKs, and AKTs). A pathway analysis confirmed the role of CREB, Calmodulin, mitogen-activated protein kinase (MAPK) and CREB modulation. Among the peptides and pathways that showed reduced phosphorylation activity, the substrates CREB, CaMK2, and CaMK4 were validated for their retinal localization and activity, using immunostaining and immunoblotting in the rd10 retina. In summary, the integrative analysis of the kinome activity and phosphoproteomic data revealed both known and novel PKG substrates in a murine IRD model. This data establishes a basis for an improved understanding of the biological pathways involved in cGMP-mediated photoreceptor degeneration. Moreover, validated PKG targets like CREB and CaMKs merit exploration as novel (surrogate) biomarkers to determine the effects of a clinical PKG-targeted treatment for IRDs.

ObjectivesNocturnal hypoxia in obstructive sleep apnoea (OSA) is a potential risk factor for cancer. We aimed to investigate the association between OSA measures and cancer prevalence in a large national patient cohort.DesignCross-sectional study.Settings44 sleep centres in Sweden.Participants62 811 patients from the Swedish registry for positive airway pressure (PAP) treatment in OSA, linked to the national cancer registry and national socioeconomic data (the course of DIsease in patients reported to Swedish CPAP, Oxygen and VEntilator RegistrY cohort).Outcome measuresAfter propensity score matching for relevant confounders (anthropometric data, comorbidities, socioeconomic status, smoking prevalence), sleep apnoea severity, measured as Apnoea-Hypopnoea Index (AHI) or Oxygen Desaturation Index (ODI), were compared between those with and without cancer diagnosis up to 5 years prior to PAP initiation. Subgroup analysis for cancer subtype was performed.ResultsOSA patients with cancer (n=2093) (29.8% females, age 65.3 (SD 10.1) years, body mass index 30 (IQR 27–34) kg/m2) had higher median AHI (n/hour) (32 (IQR 20–50) vs 30 (IQR 19–45), n/hour, p=0.002) and median ODI (n/hour) (28 (IQR 17–46) vs 26 (IQR 16–41), p<0.001) when compared with matched OSA patients without cancer. In subgroup analysis, ODI was significantly higher in OSA patients with lung cancer (N=57; 38 (21–61) vs 27 (16-43), p=0.012)), prostate cancer (N=617; 28 (17–46) vs 24, (16–39)p=0.005) and malignant melanoma (N=170; 32 (17–46) vs 25 (14–41),p=0.015).ConclusionsOSA mediated intermittent hypoxia was independently associated with cancer prevalence in this large, national cohort. Future longitudinal studies are warranted to study the potential protective influence of OSA treatment on cancer incidence.

PurposeDespite data showing breathlessness to be more prevalent in older adults, we have little detail about the severity or multidimensional characteristics of breathlessness and other self-reported measures (such as quality of life and other cardiorespiratory-related symptoms) in this group at the population level. We also know little about the relationship between multidimensional breathlessness, other symptoms, comorbidities and future clinical outcomes such as quality of life, hospitalisation and mortality. This paper reports the design and descriptive findings from the first two waves of a longitudinal prospective cohort study in older adults.ParticipantsBetween 2010 and 2011, 1900 men in a region in southern Sweden aged 65 years were invited to attend for VAScular and Chronic Obstructive Lung disease (VASCOL) baseline (Wave 1) assessments which included physiological measurements, blood sampling and a self-report survey of lifestyle and previous medical conditions. In 2019, follow-up postal survey data (Wave 2) were collected with additional self-report measures for breathlessness, other symptoms and quality of life. At each wave, data are cross-linked with nationwide Swedish registry data of diseases, treatment, hospitalisation and cause of death.Findings to date1302/1900 (68%) of invited men participated in Wave 1, which include 56% of all 65-year-old men in the region. 5% reported asthma, 2% chronic obstructive pulmonary disease, 56% hypertension, 10% diabetes and 19% had airflow limitation. The VASCOL cohort had comparable characteristics to those of similarly aged men in Sweden. By 2019, 109/1302 (8.4%) had died. 907/1193 (76%) of the remainder participated in Wave 2. Internal data completeness of 95% or more was achieved for most Wave 2 measures.Future plansA third wave will be conducted within 4 years, and the cohort will be followed through repeated follow-ups planned every fourth year, as well as national registry data of diagnosis, treatments and cause of death.