Browsing by Subject "PATHOPHYSIOLOGY"

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  • Vakkilainen, Svetlana; Mäkitie, Riikka; Klemetti, Paula; Valta, Helena; Taskinen, Mervi; Husebye, Eystein Sverre; Mäkitie, Outi (2018)
    Background: Mutations in RMRP, encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases. Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies. Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy. Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6-73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases (X-(2)(2) = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients. Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation.
  • Wielaender, F.; James, F. M. K.; Cortez, M. A.; Kluger, G.; Nessler, J. N.; Tipold, A.; Lohi, H.; Fischer, A. (2018)
    Myoclonic epilepsy in Rhodesian Ridgeback (RR) dogs is characterized by myoclonic seizures occurring mainly during relaxation periods, a juvenile age of onset and generalized tonic-clonic seizures in one-third of patients. An 8-month-old female intact RR was presented for myoclonic seizures and staring episodes that both started at 10 weeks of age. Testing for the DIRAS1 variant indicated a homozygous mutant genotype. Unsedated wireless video-electroencephalography (EEG) identified frequent, bilaterally synchronous, generalized 4 Hz spike-and-wave complexes (SWC) during the staring episodes in addition to the characteristic myoclonic seizures with generalized 4-5 Hz SWC or 4-5 Hz slowing. Photic stimulation did not evoke a photoparoxysmal response. Repeat video-EEG 2 months after initiation of levetiracetam treatment disclosed a >95% decrease in frequency of myoclonic seizures, and absence seizures were no longer evident. Absence seizures represent another seizure type in juvenile myoclonic epilepsy (JME) in RR dogs, which reinforces its parallels to JME in humans.
  • Kurtelius, Arttu; Väntti, Nelli; Jahromi, Behnam Rezai; Tähtinen, Olli; Manninen, Hannu; Koskenvuo, Juha; Tulamo, Riikka; Kotikoski, Satu; Nurmonen, Heidi; Kämäräinen, Olli-Pekka; Huttunen, Terhi; Huttunen, Jukka; Fraunberg, Mikael von Und Zu; Koivisto, Timo; Jääskeläinen, Juha E.; Lindgren, Antti E. (2019)
    Background-Varying degrees of co-occurrence of intracranial aneurysms (IA) and aortic aneurysms (AA) have been reported. We sought to compare the risk for AA in fusiform intracranial aneurysms (fIA) and saccular intracranial aneurysms (sIA) disease and evaluate possible genetic connection between the fIA disease and AAs. Additionally, the characteristics and aneurysms of the fIA and sIA patients were compared. Methods and Results-The Kuopio Intracranial Aneurysm Database includes all 4253 sIA and 125 fIA patients from its Eastern Finnish catchment population, and 13 009 matched population controls and 18 455 first-degree relatives to the IA patients were identified, and the Finnish national registers were used to identify the individuals with AA. A total of 33 fIA patients were studied using an exomic gene panel of 37 genes associated with AAs. Seventeen (14.4%) fIA patients and 48 (1.2%) sIA patients had a diagnosis of AA. Both fIA and sIA patients had AAs significantly more often than their controls (1.2% and 0.5%) or relatives (0.9% and 0.3%). In a competing risks Cox regression model, the presence of fIA was the strongest risk factor for AA (subdistribution hazard ratio 7.6, 95% CI 3.9-14.9, P Conclusions-The prevalence of AAs is increased slightly in sIA patients and significantly in fIA patients. fIA patients are older and have more comorbid diseases than sIA patients but this alone does not explain their clinically significant AA risk.
  • Tosetto, Alberto; Badiee, Zahra; Baghaipour, Mohammad-Reza; Baronciani, Luciano; Battle, Javier; Berntorp, Erik; Bodo, Imre; Budde, Ulrich; Castaman, Giancarlo; Eikenboom, Jeroen C. J.; Eshghi, Peyman; Ettorre, Cosimo; Goodeve, Anne; Goudemand, Jenny; Richard, Charles; Hay, Morris; Hoorfar, Hamid; Karimi, Mehran; Keikhaei, Bijan; Lassila, Riitta; Leebeek, Frank W. G.; Fernandez, Maria Fernanda Lopez; Mannucci, Pier Mannuccio; Mazzucconi, Maria Gabriella; Morfini, Massimo; Oldenburg, Johannes; Peake, Ian; Lopez, Rafael Parra; Peyvandi, Flora; Schneppenheim, Reinhard; Tiede, Andreas; Toogeh, Gholamreza; Trossaert, Marc; Zekavat, Omidreza; Zetterberg, Eva M. K.; Federici, Augusto B. (2020)
    Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels <20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.
  • Palmu, Samuel; Kuneinen, Susanna; Kautiainen, Hannu; Eriksson, Johan G.; Korhonen, Päivi E. (2021)
    Background and aims: Current guidelines on prediabetes and diabetes (T2D) recommend to regularly perform an oral glucose tolerance test (OGTT) on subjects at risk of T2D. However, it is not known why women tend to have relatively higher 2-h post-load plasma (2hPG) glucose concentrations during OGTT than men. The aim of the present study is to investigate if there are sex differences in fasting plasma glucose (FPG) and 2hPG concentrations in relation to body size in apparently healthy non-diabetic subjects with normal glucose tolerance. We hypothesized that sex differences in glucose tolerance are physiological and related to different body surface area (BSA) in men and women. Methods and results: A 2-h 75 g OGTT was performed on 2010 subjects aged 45-70 years. Their BSA was calculated using the Mosteller formula. Men and women were separately divided into five BSA levels. Within the normal 2hPG range, women had higher mean 2hPG concentrations during the OGTT than men in all BSA levels estimated by sex-standardized BSA (p for linearity < 0.001). BSA adjusted for age, waist circumference, leisure-time physical activity, and smoking, showed an inverse association with 2hPG concentration in both sexes. Mean FPG concentrations were higher in men than in women. Conclusions: Body size has a negative inverse association with 2hPG concentration in an OGTT even within a physiological plasma glucose range. This may cause underestimation of glucose disorders in individuals with larger BSA and overestimation in individuals with smaller BSA when using an OGTT. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  • Tarkiainen, Mika; Sipola, Petri; Jalanko, Mikko; Helio, Tiina; Laine, Mika; Jarvinen, Vesa; Hayrinen, Kaisu; Lauerma, Kirsi; Kuusisto, Johanna (2016)
    Background: Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well as in unselected consecutive patients with HCM, and respective controls. Methods: Anterior mitral valve leaflet (AML) and posterior mitral valve leaflet (PML) lengths were measured by CMR in 47 subjects with the Q1061X mutation in the gene encoding MYBPC3 and in 20 healthy relatives without the mutation. In addition, mitral valve leaflet lengths were measured by CMR in 80 consecutive non-genotyped patients with HCM in CMR and 71 age-and gender-matched healthy subjects. Results: Of the subjects with the MYBPC-Q1016X mutation, 32 had left ventricular hypertrophy (LVH, LV maximal wall thickness >= 13 mm in CMR) and 15 had no hypertrophy. PML was longer in patients with the MYBPC3-Q1061X mutation and LVH than in controls of the MYBPC group (12.8 +/- 2.8 vs 10.6 +/- 1.9 mm, P = 0.013), but the difference between the groups was not statistically significant when PML was indexed for BSA (P = 0.066), or when PML length was adjusted for BSA, age, gender, LV mass and ejection fraction (P = 0.195). There was no significant difference in the PML length in mutation carriers without LVH and controls (11.1 +/- 3.4 vs 10.6 +/- 1.9, P = 0.52). We found no difference in AML lengths between the MYBPC mutation carriers with or without hypertrophy and controls. In 80 consecutive non-genotyped patients with HCM, there was no difference either in AML or PML lengths in subjects with HCM compared to respective control subjects. Conclusions: In subjects with HCM caused by the Q1061X mutation in the MYBPC3 gene, the posterior mitral valve leaflets may be elongated, but mitral valve elongation does not constitute primary phenotypic expression of the disease. Instead, elongated mitral valve leaflets seem to be associated with body size and left ventricular remodeling.
  • Wibroe, Morten; Cappelen, Johan; Castor, Charlotte; Clausen, Niels; Grillner, Pernilla; Gudrunardottir, Thora; Gupta, Ramneek; Gustavsson, Bengt; Heyman, Mats; Holm, Stefan; Karppinen, Atte; Klausen, Camilla; Lönnqvist, Tuula; Mathiasen, Rene; Nilsson, Pelle; Nysom, Karsten; Persson, Karin; Rask, Olof; Schmiegelow, Kjeld; Sehested, Astrid; Thomassen, Harald; Tonning-Olsson, Ingrid; Zetterqvist, Barbara; Juhler, Marianne (2017)
    Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.
  • Strawbridge, Rona J.; Silveira, Angela; den Hoed, Marcel; Gustafsson, Stefan; Luan, Jian'an; Rybin, Denis; Dupuis, Josee; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gadin, Jesper R.; Backlund, Alexandra; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve E.; Kurl, Sudhir; Langenberg, Claudia; Lannfelt, Lars L.; Lind, Lars; Lindgren, Cecilia C. M.; Mannarino, Elmo; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renee; Rauramaa, Rainer; Saliba-Gustafsson, Peter; Sennblad, Bengt; Smit, Andries J.; Syvanen, Ann-Christine; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Bjorn; Bjorck, Hanna M.; Eriksson, Johan G.; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Wouter; Florez, Jose C.; Wareham, Nicholas J.; Meigs, James B.; Ingelsson, Erik; Baldassarre, Damiano; Hamsten, Anders; IMPROVE Study Grp (2017)
    Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
  • Cruz, Gabriela; Grent-'t-Jong, Tineke; Krishnadas, Rajeev; Palva, J. Matias; Palva, Satu; Uhlhaas, Peter J. (2021)
    Long-Range Temporal Correlations (LRTCs) index the capacity of the brain to optimally process information. Previous research has shown that patients with chronic schizophrenia present altered LRTCs at alpha and beta oscillations. However, it is currently unclear at which stage of schizophrenia aberrant LRTCs emerge. To address this question, we investigated LRTCs in resting-state magnetoencephalographic (MEG) recordings obtained from patients with affective disorders and substance abuse (clinically at low-risk of psychosis, CHR-N), patients at clinical high-risk of psychosis (CHR-P) (n = 115), as well as patients with a first episode (FEP) (n = 25). Matched healthy controls (n = 47) served as comparison group. LRTCs were obtained for frequencies from 4 to 40 Hz and correlated with clinical and neuropsychological data. In addition, we examined the relationship between LRTCs and transition to psychosis in CHR-P participants, and the relationship between LRTC and antipsychotic medication in FEP participants. Our results show that participants from the clinical groups have similar LRTCs to controls. In addition, LRTCs did not correlate with clinical and neurocognitive variables across participants nor did LRTCs predict transition to psychosis. Therefore, impaired LRTCs do not reflect a feature in the clinical trajectory of psychosis. Nevertheless, reduced LRTCs in the beta-band over posterior sensors of medicated FEP participants indicate that altered LRTCs may appear at the onset of the illness. Future studies are needed to elucidate the role of anti-psychotic medication in altered LRTCs.
  • Koroleva, Ksenia; Gafurov, Oleg; Guselnikova, Valeriia; Nurkhametovez, Dilyara; Giniatullina, Raisa; Sitdikova, Guzel; Mattila, Olli S.; Lindsberg, Perttu J.; Malm, Tarja Maarit; Giniatullin, Rashid (2019)
    Peripheral mechanisms of primary headaches such as a migraine remain unclear. Meningeal afferents surrounded by multiple mast cells have been suggested as a major source of migraine pain. Extracellular ATP released during migraine attacks is a likely candidate for activating meningeal afferents via neuronal P2X receptors. Recently, we showed that ATP also increased degranulation of resident meningeal mast cells (Nurkhametova et al., 2019). However, the contribution of ATP-induced mast cell degranulation in aggravating the migraine pain remains unknown. Here we explored the role of meningeal mast cells in the pro-nociceptive effects of extracellular ATP. The impact of mast cells on ATP mediated activation of peripheral branches of trigeminal nerves was measured electrophysiologically in the dura mater of adult wild type (WT) or mast cell deficient mice. We found that a spontaneous spiking activity in the meningeal afferents, at baseline level, did not differ in two groups. However, in WT mice, meningeal application of ATP dramatically (24.6-fold) increased nociceptive firing, peaking at frequencies around 10 Hz. In contrast, in mast cell deficient animals, ATP-induced excitation was significantly weaker (3.5-fold). Application of serotonin to meninges in WT induced strong spiking. Moreover, in WT mice, the 5-HT3 antagonist MDL-7222 inhibited not only serotonin but also the ATP induced nociceptive firing. Our data suggest that extracellular ATP activates nociceptive firing in meningeal trigeminal afferents via amplified degranulation of resident mast cells in addition to direct excitatory action on the nerve terminals. This highlights the importance of mast cell degranulation via extracellular ATP, in aggravating the migraine pain.
  • Lindström, Mikael; Valkonen, Miia; Tohmola, Niina; Renkonen, Risto; Strandin, Tomas; Vaheri, Antti; Itkonen, Outi (2019)
    Background: Bradykinin is an important mediator of inflammation and vascular permeability and could have an important role in the development of septic shock. Measurement of bradykinin by immunological methods may suffer from interference and lack of specificity. We developed and validated a liquid chromatography mass spectrometry assay (LC-MS/MS) for plasma bradykinin. Methods: We used plasma samples from healthy volunteers (n = 19) and patients with septic shock (n = 47). Stable isotope bradykinin internal standard was added to samples before solid-phase extraction and quantification by LC-MS/MS. Stability of bradykinin was studied for 12 months. Results: Our assay has good sensitivity (0.1 nmol/l) and a wide linear range (0.1-1000 nmol/1). Bradykinin added to plasma was stable for 12 months at -20 degrees C when a mixture of protease inhibitors was added at sampling but degraded during repeated freezing and thawing. Bradykinin concentration in plasma from septic shock patients (<0.1-0.6 nmol/l) did not change significantly during shock and recovery but differed slightly from that in healthy individuals (0.5-1.1 nmol/1). Conclusions: Our bradykinin assay was successfully used to determine bradykinin concentrations in plasma samples. Intensive care unit patients with septic shock had low concentrations of plasma bradykinin during both shock and recovery phases.
  • Ollila, Aino; Virolainen, Juha; Vanhatalo, Joonas; Vikatmaa, Pirkka; Tikkanen, Ilkka; Venermo, Maarit; Salmenpera, Markku; Pettila, Ville; Vikatmaa, Leena (2017)
    Objectives: Elderly patients undergoing vascular surgery are at major risk for perioperative cardiac complications. The authors investigated continuous electrocardiographic Holter monitoring in a postoperative setting to determine the degree of postoperative ischemic load and its possible associations with perioperative myocardial infarction. Design: A prospective, observational study. Setting: One university hospital. Participants: The study comprised 51 patients aged 65 years or older undergoing peripheral arterial surgery. Interventions: Continuous electrocardiographic monitoring with a Holier device was started postoperatively and continued for 72 hours or until discharge. Postural changes were recorded using a 3-axis accelerometer. Standard 12-lead electrocardiography, high-sensitive troponin T measurements, and an inquiry of ischemic symptoms were performed 4 times perioperatively. Measurements and Main Results: The primary outcomes were ischemic load (area under the function of ischemic ST-segment deviation and ischemic time) and perioperative myocardial infarction. During 3,262.7 patient-hours of monitoring, 17 patients (33.3%) experienced 608 transient ischemic events, all denoted by ST-segment depression. Of these 17 patients, 5 experienced perioperative myocardial infarction. The mean ischemic load in all patients was 913.2 +/- 2,797.3 mu V x minute. Ischemic load predicted perioperative myocardial infarction, with an area under receiver operating characteristics curve (95% confidence interval) of 0.87 (0.75-0.99). Ischemic changes occurred most frequently during hours 24 to 60 of monitoring. Ischemia was asymptomatic in 14 of 17 patients (82.4%). Conclusion: Postoperative myocardial ischemia was common in peripheral vascular surgery patients and may progress to perioperative myocardial infarction. Ischemic load was a good predictor of perioperative myocardial infarction. Ambulatory electrocardiographic monitoring solutions for continuous postoperative ischemia detection are warranted in the surgical ward. (C) 2017 Elsevier Inc. All rights reserved.
  • Rugemalira, Emilie; Roine, Irmeli; Kuligowski, Julia; Sanchez-Illana, Angel; David Pineiro-Ramos, Jose; Andersson, Sture; Peltola, Heikki; Leite Cruzeiro, Manuel; Pelkonen, Tuula; Vento, Maximo (2019)
    The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2'-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO(2)-Tyr) and 8-oxo-2'-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p <0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO(2)-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.
  • Kotkansalo, Anna; Leinonen, Ville; Korajoki, Merja; Salmenkivi, Jyrki; Korhonen, Katariina; Malmivaara, Antti (2019)
    Background The incidence of surgery for degenerative cervical spine disease (DCSD) has risen by almost 150% in the USA in the last three decades and stabilized at slightly over 70 operations/100,000 people. There has been significant regional variation in the operation incidences. We aim to assess the diagnosis-based, age-adjusted trends in the operation incidences and the regional variation in Finland between 1999 and 2015. Methods Data from the Finnish Hospital Discharge Register (FHDR), the Cause of Death Register, and the registers of the Social Insurance Institution were combined to analyze all the primary operations for DCSD or rheumatoid atlanto-axial subluxation (rAAS). Combinations of the operative and the diagnosis codes were used to classify the patients into five diagnostic groups. Results A total of 19,701 primary operations were included. The age-adjusted operation incidence rose from 21.0 to 36.5/100,000 people between 1999 and 2013 and plateaued thereafter. The incidence of surgery for radiculopathy increased from 13.1 to 23.3 operations/100,000 people, and the incidence of surgery for DCM increased from 5.8 to 7.0 operations/100,000 people. The rise was especially pronounced in surgery for foraminal stenosis, which increased from 5.3 to 12.4 operations/100,000 people. Of the five diagnostic groups, only operations for rAAS declined. Operations increased especially in the 40- to 65-year-old age group. The overall operation incidences varied from 18.3 to 43.1 operations/100,000 people between the university hospitals. Conclusions The age-adjusted incidence of surgery for DCSD has risen in Finland by 76%, but the rise has plateaued. Surgery for radiculopathy, especially for foraminal stenosis, increased more steeply than surgery for degenerative medullopathy, with vast regional differences in the operation incidences.