Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function. The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome. In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Post-COVID sequelae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa.

The post-viral fatigue syndromes long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have multiple, potentially overlapping, pathological processes. These include persisting reservoirs of virus, e.g., SARS-CoV-2 in long COVID patient's tissues, immune dysregulation with or without reactivation of underlying pathogens, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV6), as we recently described in ME/CFS, and possibly yet unidentified viruses. In the present study we tested saliva samples from two cohorts for IgG against human adenovirus (HAdV): patients with ME/CFS (n = 84) and healthy controls (n = 94), with either mild/asymptomatic SARS-CoV-2 infection or no infection. A significantly elevated anti-HAdV IgG response after SARS-CoV-2 infection was detected exclusively in the patient cohort. Longitudinal/time analysis, before and after COVID-19, in the very same individuals confirmed HAdV IgG elevation after. In plasma there was no HAdV IgG elevation. We conclude that COVID-19 triggered reactivation of dormant HAdV in the oral mucosa of chronic fatigue patients indicating an exhausted dysfunctional antiviral immune response in ME/CFS, allowing reactivation of adenovirus upon stress encounter such as COVID-19. These novel findings should be considered in clinical practice for identification of patients that may benefit from therapy that targets HAdV as well.

Defining post-acute COVID-19 syndrome (PACS) by an epigenetic biosignature in peripheral blood mononuclear cells.

Post-acute COVID-19 syndrome (PACS) has been defined as symptoms persisting after clearance of a COVID-19 infection. We have previously demonstrated that alterations in DNA methylation (DNAm) status persist in individuals who recovered from a COVID-19 infection, but it is currently unknown if PACS is associated with epigenetic changes. We compared DNAm patterns in patients with PACS with those in controls and in healthy COVID-19 convalescents and found a unique DNAm signature in PACS patients. This signature unravelled modified pathways that regulate angiotensin II and muscarinic receptor signalling and protein-protein interaction networks that have bearings on vesicle formation and mitochondrial function.

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts. Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva. Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs. Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2 in vivo and in vitro.

A majority of SARS-CoV-2 recoverees develop only mild-to-moderate symptoms, while some remain completely asymptomatic. Although viruses, including SARS-CoV-2, may evade host immune responses by epigenetic mechanisms including DNA methylation, little is known about whether these modifications are important in defence against and healthy recovery from COVID-19 in the host. To this end, epigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents, and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated in vitro with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation, and module identification analyses. Differential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified in vivo, comprising 66 genes of which six (TP53, INS, HSPA4, SP1, ESR1, and FAS) were present in corresponding in vitro analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling, and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. Altered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. Both in vitro and in vivo exposure caused epigenetic modulation of pathways thataffect odour perception. Future studies should determine whether this reflects host-induced protective antiviral defense or targeted viral hijacking to evade host defence.

Protein tau concentration in blood increases after SCUBA diving: an observational study.

PURPOSE: It is speculated that diving might be harmful to the nervous system. The aim of this study was to determine if established markers of neuronal injury were increased in the blood after diving. METHODS: Thirty-two divers performed two identical dives, 48 h apart, in a water-filled hyperbaric chamber pressurized to an equivalent of 42 m of sea water for 10 min. After one of the two dives, normobaric oxygen was breathed for 30 min, with air breathed after the other. Blood samples were obtained before and at 30-45 and 120 min after diving. Concentrations of glial fibrillary acidic, neurofilament light, and tau proteins were measured using single molecule array technology. Doppler ultrasound was used to detect venous gas emboli. RESULTS: Tau was significantly increased at 30-45 min after the second dive (p < 0.0098) and at 120 min after both dives (p < 0.0008/p < 0.0041). Comparison of matching samples showed that oxygen breathing after diving did not influence tau results. There was no correlation between tau concentrations and the presence of venous gas emboli. Glial fibrillary acidic protein was decreased 30-45 min after the first dive but at no other point. Neurofilament light concentrations did not change. CONCLUSIONS: Tau seems to be a promising marker of dive-related neuronal stress, which is independent of the presence of venous gas emboli. Future studies could validate these results and determine if there is a quantitative relationship between dive exposure and change in tau blood concentration.

Biomarkers of neuronal damage in saturation diving-a controlled observational study.

PURPOSE: A prospective and controlled observational study was performed to determine if the central nervous system injury markers glial fibrillary acidic protein (GFAp), neurofilament light (NfL) and tau concentrations changed in response to a saturation dive. METHODS: The intervention group consisted of 14 submariners compressed to 401 kPa in a dry hyperbaric chamber. They remained pressurized for 36 h and were then decompressed over 70 h. A control group of 12 individuals was used. Blood samples were obtained from both groups before, during and after hyperbaric exposure, and from the intervention group after a further 25-26 h. RESULTS: There were no statistically significant changes in the concentrations of GFAp, NfL and tau in the intervention group. During hyperbaric exposure, GFAp decreased in the control group (mean/median - 15.1/ - 8.9 pg·mL-1, p < 0.01) and there was a significant difference in absolute change of GFAp and NfL between the groups (17.7 pg·mL-1, p = 0.02 and 2.34 pg·mL-1, p = 0.02, respectively). Albumin decreased in the control group (mean/median - 2.74 g/L/ - 0.95 g/L, p = 0.02), but there was no statistically significant difference in albumin levels between the groups. In the intervention group, haematocrit and mean haemoglobin values were slightly increased after hyperbaric exposure (mean/median 2.3%/1.5%, p = 0.02 and 4.9 g/L, p = 0.06, respectively). CONCLUSION: Hyperbaric exposure to 401 kPa for 36 h was not associated with significant increases in GFAp, NfL or tau concentrations. Albumin levels, changes in hydration or diurnal variation were unlikely to have confounded the results. Saturation exposure to 401 kPa seems to be a procedure not harmful to the central nervous system. TRIAL REGISTRATION: ClinicalTrials.gov NCT03192930.

Sizing Up Extracellular DNA: Instant Chromatin Discharge From Cells When Placed in Serum-Free Conditions.

How do you wash cells? Three out of four of our colleagues use experimental procedures during everyday lab-bench work that can severely impair data interpretation depending on how cells are handled. We show here that a subpopulation (2-3%) of human leukocytes immediately induce a yet unclassified lytic cell death, concomitant with discharge of chromatin entities and cell elimination, when placed in protein-free solutions (i.e., PBS and HBSS). DNA release was not restricted to hematopoietic cells but occurred also in HEK293T cells. Albumin, fetal bovine serum, polyethylene glycol, and Pluronic F-68 supplements prevented chromatin discharge. Expelled chromatin was devoid of surrounding membranes but maintained its original nuclear shape, although ∼10 times enlarged. These structures differed from DNA appearance after osmotic or detergent-induced cell lysis. Besides sounding a cautionary note to the neutrophil extracellular trap (NET) research community, in which ∼50% of all published studies used protein-free media for NET-formation, our study also provides a rapid tool for analysis of chromatin organization.

Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies.

Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.

Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial.

BACKGROUND: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. METHODS: We did a randomised, controlled, phase 2-3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen-A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18-80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30-40 sessions, 100% oxygen, breathed at a pressure of 240-250 kPa, for 80-90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6-8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. FINDINGS: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210-262) in the hyperbaric oxygen therapy group and 217 days (195-237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2-18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1-2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. INTERPRETATION: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. FUNDING: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.

Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.

Patient's characteristics and outcomes in necrotising soft-tissue infections: results from a Scandinavian, multicentre, prospective cohort study.

PURPOSE: Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and high rates of morbidity and mortality, but our knowledge is primarily derived from small prospective studies and retrospective studies. METHODS: We performed an international, multicentre, prospective cohort study of adults with NSTI describing patient's characteristics and associations between baseline variables and microbiological findings, amputation, and 90-day mortality. RESULTS: We included 409 patients with NSTI; 402 were admitted to the ICU. Cardiovascular disease [169 patients (41%)] and diabetes [98 (24%)] were the most common comorbidities; 122 patients (30%) had no comorbidity. Before surgery, bruising of the skin [210 patients (51%)] and pain requiring opioids [172 (42%)] were common. The sites most commonly affected were the abdomen/ano-genital area [140 patients (34%)] and lower extremities [126 (31%)]. Monomicrobial infection was seen in 179 patients (44%). NSTI of the upper or lower extremities was associated with monomicrobial group A streptococcus (GAS) infection, and NSTI located to the abdomen/ano-genital area was associated with polymicrobial infection. Septic shock [202 patients (50%)] and acute kidney injury [82 (20%)] were common. Amputation occurred in 22% of patients with NSTI of an extremity and was associated with higher lactate level. All-cause 90-day mortality was 18% (95% CI 14-22); age and higher lactate levels were associated with increased mortality and GAS aetiology with decreased mortality. CONCLUSIONS: Patients with NSTI were heterogeneous regarding co-morbidities, initial symptoms, infectious localisation, and microbiological findings. Higher age and lactate levels were associated with increased mortality, and GAS infection with decreased mortality.

Serum tau concentration after diving - an observational pilot study.

INTRODUCTION: Increased concentrations of tau protein are associated with medical conditions involving the central nervous system, such as Alzheimer's disease, traumatic brain injury and hypoxia. Diving, by way of an elevated ambient pressure, can affect the nervous system, however it is not known whether it causes a rise in tau protein levels in serum. A prospective observational pilot study was performed to investigate changes in tau protein concentrations in serum after diving and also determine their relationship, if any, to the amount of inert gas bubbling in the venous blood. METHODS: Subjects were 10 navy divers performing one or two dives per day, increasing in depth, over four days. Maximum dive depths ranged from 52-90 metres' sea water (msw). Air or trimix (nitrogen/oxygen/helium) was used as the breathing gas and the oxygen partial pressure did not exceed 160 kPa. Blood samples taken before the first and after the last dives were analyzed. Divers were monitored for the presence of venous gas emboli (VGE) at 10 to15 minute intervals for up to 120 minutes using precordial Doppler ultrasound. RESULTS: Median tau protein before diving was 0.200 pg·mL⁻¹ (range 0.100 to 1.10 pg·mL⁻¹) and after diving was 0.450 pg·mL⁻¹ (range 0.100 to 1.20 pg·mL⁻¹; P = 0.016). Glial fibrillary acidic protein and neurofilament light protein concentrations analyzed in the same assay did not change after diving. No correlation was found between serum tau protein concentration and the amount of VGE. CONCLUSION: Repeated diving to between 52-90 msw is associated with a statistically significant increase in serum tau protein concentration, which could indicate neuronal stress.

Immunological and Quality-of-Life Profiles in Women with Breast Cancer: Complementary versus Conventional Care.

BACKGROUND: Previous studies showed that women with breast cancer treated in anthroposophic clinic versus conventional care had increased quality of life (QoL) parameters, fighting spirit, and anxiety coping. We have now analyzed immune and QoL factors in these 2 groups for possible differences during the first 6 months after admission, prompted by anthroposophic studies, including mistletoe extracts, showing beneficial immune system effects. PATIENTS AND METHODS: Fourteen immunological variables, including leukocyte count, lymphocyte count, activated T cells (CD4+ and CD8+), NK cells, B cells, IL1ß, IL6, IL10, and oxytocin, were longitudinally analyzed in both groups (n = 2 × 26). A panel of QoL parameters were analyzed using 3 different instruments. Statistical evaluation included that each patient was its own control. RESULTS: Cytotoxic CD8+ T cell frequency (percent of lymphocytes analyzed by flow-cytometry) significantly decreased over time in the anthroposophic group versus the conventional group (repeated measures ANOVA, p = 0.05). No major differences were observed in other immunological parameters, whereas QoL variables, anxiety decreased and physical symptoms increased/improved significantly in the anthroposophic group (p = 0.04 and p = 0.05, respectively). CONCLUSION: Overall, women with breast cancer in anthroposophic or conventional therapy did not differ in their immune profiles over time, with exception of decreased cytotoxic T cells in the anthroposophic group. Improvement in physical symptoms along with less anxiety in this group may have influenced the brain-immune axis resulting in lower frequency of CD8+ T cells, a feature associated with less aggressive cancer stages. To evaluate whether this observation is associated with good or bad prognosis, further detailed analyses of memory and naïve CD8+ T cells at tumor site and in blood circulation are essential.

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model.

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C.

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Natural IgM antibodies in the immune defence against neoehrlichiosis.

BACKGROUND: Neoehrlichiosis is an infectious disease caused by the tick-borne bacterium "Candidatus Neoehrlichia mikurensis". Splenectomy and rituximab therapies are risk factors for severe neoehrlichiosis. Our aim was to examine if neoehrlichiosis patients had low levels of natural IgM antibodies and/or were hypogammaglobulinemic, and if such deficiencies were associated with asplenia and vascular complications. METHODS: Neoehrlichiosis patients (n = 9) and control subjects (n = 10) were investigated for serum levels of IgG, IgA, and IgM, and for levels of natural IgM antibodies to pneumococcal polysaccharides (6B, 14), and to the malondialdehyde acetaldehyde epitope of oxidized LDL. The multivariate method Projection to Latent Structures was used to analyze the data. RESULTS: The levels of natural IgM antibodies of various specificities were decreased or not measurable in half of the studied patients with neoehrlichiosis. Only one patient and one control subject were hypogammaglobulinemic. An inverse relationship was noted between the levels of natural IgM antibodies and the development of deep vein thrombosis. Unexpectedly, no association was seen between having or not having a spleen and the levels of natural IgM antibody levels in the circulation. CONCLUSIONS: Neither hypogammaglobulinemia nor lack of natural IgM antibodies alone predisposes for severe neoehrlichiosis. The importance of the spleen in the immune defence against Ca. N. mikurensis probably lies in its capacity to generate or maintain specific antibodies.

CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia.

Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients. To identify the molecular target of quercetin, we employed a new cell line, HG3, obtained by immortalization of B-cells from a chronic lymphocytic leukaemia patient at the later stage of disease. We confirmed that quercetin in association with ABT-737 synergistically enhances apoptosis in HG3 (combination index < 1 for all fractions affected). We also reported that the cellular uptake of quercetin is extremely rapid, with an intracellular concentration of about 38.5 ng/106 cells, after treatment with 25 µM for 5 min. We demonstrated that the activity of protein kinase CK2, which positively triggers PI3K/Akt pathway by inactivating PTEN phosphatase, is inhibited by quercetin immediately after its addition to HG3 cells (0-2 min). PI3K activity was also inhibited by quercetin within 60 min from the treatment. The combined inhibition of CK2 and PI3K kinase activities by quercetin restored ABT-737 sensitivity and increased lethality in human leukemia cells.

[The use of treatment table COMEX 30 for severe neurological decompression sickness]. / COMEX 30 för behandling av tryckfallssjuka med neurologiska symtom.

The use of treatment table COMEX 30 for severe neurological decompression sickness Decompression sickness (DCS) can occur after all dives. It often requires treatment in a pressure chamber. DCS with symptoms from the nervous system is particularly serious. In certain cases, the commonly used recompression table (USN TT6) does not suffice to revert severe neurological symptoms. A more advanced recompression table, COMEX 30, can be utilized in these cases. We report three cases of DCS where treatment according to COMEX 30 successfully resolved neurological symptoms. These cases illustrate the importance of fast and proper management of severe DCS and the need of hyperbaric centers staffed and equipped to give correct treatment. National coordination is paramount in order to be able to provide optimal care for both recreational and commercial divers afflicted by DCS.