Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study).

Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011-4.173, p = .046)]. However, PNPLA3 rs738409 [1.049 (0.650-1.692, p = .844)], TM6SF2 rs58542926 [0.721 (0.369-1.411, p = .340)] or MBOAT7 rs641738 [0.885 (0.543-1.439, p = .621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p = .013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.

Long-term hormonal follow-up after human Puumala hantavirus infection.

OBJECTIVE: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE. DESIGN: Forty-seven of our recent cohort of 58 NE patients volunteered to be re-examined in order to estimate the burden of hormonal deficiency 4 to 8 years after the acute illness. Two patients had suffered from pituitary haemorrhage, but many others exhibited pituitary oedema during their acute infection. In this study, we searched for symptoms of hormonal deficiency, performed hormonal laboratory screening, and most patients underwent pituitary MRI examination. RESULTS: The pituitary size had diminished in all patients in whom MRI was performed (P < 0·001). One patient with acute phase haemorrhage had made a complete recovery while the other continued to require hormonal substitution. In addition, hormonal laboratory abnormalities were observed in nine other patients; these being attributable to several reasons, for example independent peripheral hormonal diseases, side effects of medication or other secondary causes such as obesity. None of them had signs of late-onset pituitary insufficiency caused by their previous NE. Health-related quality of life (mean and median 15D score) of patients was comparable to that of age-standardized general population. CONCLUSIONS: None of our patients had developed obvious late-onset hypopituitarism despite of the fact that pituitary gland can be affected during acute NE. We recommend requesting a history of hantavirus infection whenever the possibility of pituitary dysfunction is suspected at least in patients originating from regions with high NE infection rate.

Respiratory diphtheria in an asylum seeker from Afghanistan arriving to Finland via Sweden, December 2015.

In December 2015, an asylum seeker originating from Afghanistan was diagnosed with respiratory diphtheria in Finland. He arrived in Finland from Sweden where he had already been clinically suspected and tested for diphtheria. Corynebacterium diphtheriae was confirmed in Sweden and shown to be genotypically and phenotypically toxigenic. The event highlights the importance of early case detection, rapid communication within the country and internationally as well as preparedness plans of diphtheria antitoxin availability.

Multiplex PCR for respiratory bacteria in acute care.

The purpose of the study was to evaluate the clinical utility of multiplex PCR for detecting bacterial respiratory pathogens in nasopharyngeal samples. Acutely ill adults in the emergency department with respiratory infection symptoms, fever, chest pain or poor general condition were enrolled for this cohort study. Samples were stored at -70 °C until being analysed with multiplex PCR for seven respiratory bacteria. Of the 912 patients enrolled, those with positive bacterial samples (n = 130, 14%) were significantly younger than those with a negative finding (55.5 years vs 62.2 years, p < 0.001), and their mean C-reactive protein (CRP) concentration was higher (110 mg/L vs 59 mg/L, p < 0.0001). Patients with a positive respiratory bacterial finding had a higher probability of pneumonia (35% vs 13%, p < 0.001) and a higher likelihood of receiving a prescription for antibiotics than those with a negative finding (79% vs 59%, p < 0.0001). Positive detection of Streptococcus pneumoniae was associated with a 4.5-fold risk of pneumonia in a multivariate model and detection of an atypical respiratory pathogen with a 9-fold risk. Bacterial PCR performed on nasopharyngeal samples appeared to offer a valuable addition to the diagnostics of infections in adults in acute care.

Short- and long-term effects of imatinib in hospitalized COVID-19 patients: A randomized trial.

OBJECTIVES: We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients. METHODS: Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400 mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients. RESULTS: We randomized 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year, and in SoC, 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47-3.90). At 1 year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78-1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32-1.63; low certainty evidence). CONCLUSIONS: The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalized COVID-19 patients.

Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in acute Puumala hantavirus infection.

Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is the most common hemorrhagic fever with renal syndrome (HFRS) in Europe. The infection activates immunological mechanisms that contribute to the pathogenesis and characteristics of the illness. In this study we measured cerebrospinal fluid (CSF) neopterin concentration from 23 acute-phase NE patients. We collected data on kidney function, markers of tissue permeability, haemodynamic properties, blood cell count, length of hospitalisation, inflammatory parameters, and ophthalmological properties. The neopterin levels were elevated (> 5.8 nmol/L) in 22 (96%) NE-patients (mean 45.8 nmol/L); these were especially high in patients with intrathecal PUUV-IgM production (mean 58.2 nmol/L, P = 0.01) and those with elevated CSF protein concentrations (mean 63.6 nmol/L, P < 0.05). We also observed a correlation between the neopterin and high plasma creatinine value (r = 0.66, P = 0.001), low blood thrombocyte count (r = -0.42, P < 0.05), and markedly disturbed refractory properties of an eye (r = 0.47, P < 0.05). Length of hospitalisation correlated with the neopterin (r = 0.42, P < 0.05; male patients r = 0.69, P < 0.01). Patients with signs of tissue oedema and increased permeability also had high neopterin concentrations. These results reinforce the view that PUUV-HFRS is a general infection that affects the central nervous system and the blood-brain barrier.

Signs of general inflammation and kidney function are associated with the ocular features of acute Puumala hantavirus infection.

BACKGROUND: Puumala hantavirus (PUUV) causes nephropathia epidemica (NE), a type of viral haemorrhagic fever with renal syndrome (HFRS). This febrile infection may affect the kidneys, central nervous system (CNS), and the eye. Acute illness is associated with increased tissue permeability and tissue oedema, and many patients experience reduced vision. The aim of this study was to explore the physiological events associated with the ocular features of acute NE. METHODS: This was a prospective study of 46 NE patients who were examined during the acute infection and 1 month after hospitalization. Visual acuity, refraction, intraocular pressure (IOP), and ocular dimensions were evaluated. Cerebrospinal fluid and blood samples were collected, brain magnetic resonance imaging and electroencephalography were recorded, and HLA haplotype was analyzed. The degrees of tissue oedema and fluid imbalance were evaluated. RESULTS: CNS examinations did not reveal the source of the ocular changes in acute NE. The plasma C-reactive protein concentration correlated with the lens thickness and the IOP. The plasma creatinine level was associated with the change in anterior chamber depth. However, oliguric and polyuric patients displayed similar ocular findings. Patients positive for the DR3-DQ2 haplotype experienced the least diminished visual acuity. CONCLUSIONS: The level of systemic inflammation rather than CNS involvement appears to account for the ocular changes during acute PUUV infection, and the severity of kidney dysfunction may also have a significant role. In addition, the genetic properties of the host may well explain the ocular features of acute hantavirus infection.

52-year follow-up of a birth cohort reveals a high pneumonia incidence among young men.

Background: Knowledge of pneumonia incidence and risk factors in adults is mainly based on clinical studies of selected patient data and registers with ageing populations. Prospective population-based investigations, such as birth cohort studies, are needed to understand pneumonia incidence and risk factors among young and working-age populations. Methods: Northern Finland Birth Cohort (NFBC) 1966 data (n=6750) were analysed for pneumonia incidence and risk factors. Incidence analysis was replicated using data from an independent NFBC 1986 cohort (n=9207). Pneumonia in relation to chronic conditions and lifestyle factors was analysed. Results: A peak with a maximum of 227 pneumonia episodes per 10 000 among men between the ages of 19 and 21 years was found in two independent cohorts. Pneumonia was associated with male sex (relative risk 1.72, 95% CI 1.45-2.04; p<0.001), low educational level (relative risk 2.30, 95% CI 1.72-3.09; p<0.001), smoking (relative risk 1.55, 95% CI 1.31-1.84; p<0.001), asthma (relative risk 2.19, 95% CI 1.73-2.75; p<0.001), cardiovascular diseases (relative risk 2.50, 95% CI 2.04-3.07; p=0.001), kidney diseases (relative risk 4.14, 95% CI 2.81-6.10; p<0.001), rheumatoid arthritis (relative risk 2.69, 95% CI 1.80-4.01; p<0.001), psoriasis (relative risk 2.91, 95% CI 1.92-4.41; p<0.001) and type II diabetes (relative risk 1.80, 95% CI 1.34-2.42; p<0.001). Men with excessive alcohol consumption at age 31 years were at risk of future pneumonia (relative risk 2.40, 95% CI 1.58-3.64; p<0.001). Conclusions: Birth cohort data can reveal novel high-risk subpopulations, such as young males. Our study provides understanding of pneumonia incidence and risk factors among young and working age populations.

Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms.

BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. METHODS AND RESULTS: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. CONCLUSIONS: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Young male patients are at elevated risk of developing serious central nervous system complications during acute Puumala hantavirus infection.

BACKGROUND: Our aim was to characterize clinical properties and laboratory parameters in patients with or without cerebrospinal fluid (CSF) findings suggestive of central nervous system (CNS) involvement, and especially those who developed serious CNS complications during acute nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) infection. METHODS: A prospective cohort of 40 patients with acute NE and no signs of major CNS complications was analyzed. In addition, 8 patients with major CNS complications associated with NE were characterized. We collected data of CNS symptoms, CSF analysis, brain magnetic resonance imaging (MRI) results, electroencephalography (EEG) recordings, kidney function, and a number of laboratory parameters. Selected patients were evaluated by an ophthalmologist. RESULTS: Patients with a positive CSF PUUV IgM finding or major CNS complications were more often males (p < 0.05) and they had higher plasma creatinine values (p < 0.001) compared to those with negative CSF PUUV IgM. The degree of tissue edema did not explain the CSF findings. Patients with major CNS complications were younger than those with negative CSF PUUV IgM finding (52.9 vs. 38.5 years, p < 0.05). Some patients developed permanent neurological and ophthalmological impairments. CONCLUSIONS: CNS and ocular involvement during and after acute NE can cause permanent damage and these symptoms seem to be attributable to true infection of the CNS rather than increased tissue permeability. The possibility of this condition should be borne in mind especially in young male patients.

Chest imaging findings in hospitalized patients with H1N1 influenza.

BACKGROUND: Previous studies have reported chest radiographic findings of consolidation and ground-glass opacity in patients with swine-origin influenza A (H1N1). However, most of these studies include both hospitalized and outpatients. PURPOSE: To evaluate initial chest radiographic and CT findings of hospitalized swine flu patients, adults and children, confirmed with a real-time reverse transcriptase polymerase chain reaction (PCR) assay for H1N1 virus. MATERIAL AND METHODS: All PCR-verified swine flu patients admitted to the Department of Emergency Medicine (October 1 to December 15, 2009) at Oulu University Hospital, in Northern Finland, who underwent frontal chest radiography within 24 hours of presentation and who were hospitalized, were included. The radiographs and CT scans were assessed for the presence of pneumonia and characterized by pattern and distribution. The patients' medical records were analyzed for demographics, underlying medical conditions, the admission to the intensive care unit (ICU), initiation of mechanical ventilation or non-invasive ventilation support (NIV) and death. RESULTS: Of 159 H1N1 influenza patients, 135 (85%) underwent chest radiographs at admission; 113 adults and 22 children. Findings of pulmonary infiltrates were detected in 62% (70/113) of adults and 64% (14/22) of children, being bilateral in 67% of adults and 64% of the children. The anatomic location of infiltrates was more often peripheral in adults; 42/70 (60%) vs. 4/14 (29%), P = 0.041, and diffuse among children; 9/14 (64%) vs. 26/70 (37%), P = 0.078. When the ICU and NIV patients were compared to less severe cases, on their chest radiographs four or five lobes were more often affected (65%, 11/17 vs. 34% 23/67, P = 0.029 ). The predominant radiographic findings were consolidation (93% of all patients, 91% of adults and 100% of children) and ground-glass opacity (74% of all, 77% of adults and 57% of children). Pulmonary emboli were detected by CT in 2/9 (22%) patients. CONCLUSION: The pandemic 2009 swine influenza causes common and widely distributed infiltrates on chest radiographs among hospitalized patients, which are not peculiar to usual respiratory viral infections, and these findings can not be differentiated from usual bacterial pneumonia.

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection.

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.

[Influenza A(H1N1)v-patients treated in Oulu University hospital]. / Oulun yliopistollisessa sairaalassa hoidetut influenssa a(H1N1)v-potilaat.

BACKGROUND: In Finland, the pandemic A(H1N1)v-influenza was experienced in late 2009. MATERIAL AND METHODS: A(H1N1)v-patients hospitalized in Oulu University Hospital were evaluated. RESULTS: Altogether, 159 A(H1N1)v-patients, including 37 children, were hospitalized. Their median age was 35. Eighteen (11 %) patients required admission to ICU; three of them died. As many as 62% of the patients suffered from radiologically confirmed pneumonia. The incidences of hospitalization, ICU care and death were 40,5, 4,6 and 0,8 per 100000, respectively. CONCLUSIONS: Despite the low mortality rate, a rather high number of patients required hospitalization. Findings in chest radiography were common and prominent.

Low-density lipoprotein clearance in patients with chronic renal failure.

BACKGROUND: Chronic renal failure increases the risk of atherosclerosis. The clearance of low-density lipoprotein (LDL), a major risk factor for atherosclerosis, has been reported as being disturbed in dialysis patients. We studied LDL metabolism in non-dialyzed patients with chronic kidney disease (CKD). METHODS: LDL clearance was studied with a radiotracer method in 57 CKD patients and 10 healthy controls. RESULTS: In the CKD patients, the fractional catabolic rate of LDL apo B (LDL FCR), an indicator of LDL clearance from plasma, ranged from 0.13 to 0.56 pools/day with a mean value of 0.34 pools/day being comparable to that of the control subjects. In the renal patients, LDL FCR correlated significantly with estimated glomerular filtration rate (eGFR) (r = 0.340, P = 0.010) and this association remained significant after the adjustment with age, body mass index, gender, presence of diabetes and LDL cholesterol concentration (P = 0.004). In CKD patients with eGFR <15 mL/min/1.73 m(2) the mean LDL FCR was significantly reduced when compared to that of CKD patients with eGFR >30 mL/min/1.73 m(2) (P = 0.005). LDL apo B production rate was not associated with renal function or different between renal patients and control subjects. CONCLUSIONS: The clearance of LDL seems to be related to the severity of renal impairment, but a remarkable reduction in LDL catabolism can be observed only in patients with advanced renal failure.

Variation in the vascular endothelial growth factor gene, carotid intima-media thickness and the risk of acute myocardial infarction.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor, but its role in atherogenesis is still unclear. Our goal was to study whether three variants of the VEGF gene, previously associated with VEGF production, are linked to atherosclerosis defined as carotid intima-media thickness (IMT) and as the risk of acute myocardial infarction (AMI). MATERIAL AND METHODS: Three VEGF gene single nucleotide polymorphisms (SNPs) (-2578A>C rs699947, -634C>G rs2010963 and +936C>T rs3025039) were genotyped in 516 control subjects of the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort and in 251 survivors of AMI. In the OPERA cohort, the genotyped SNPs were analysed for their association with IMT. The SNPs were also analysed for their association with the risk of AMI, a complication of advanced atherosclerosis. In addition, haplotype frequencies and their associated effects on IMT and on the risk of AMI were estimated. RESULTS: None of the single genotyped polymorphisms was significantly associated with overall IMT or with the risk of AMI. However, the haplotype CCC was associated with higher overall IMT without plaques in women (p = 0.01, haplotypic effect +0.03 mm), the haplotype CCT with higher IMT without plaques in the internal carotid artery in men (p = 0.001, +0.11), while the haplotype AGT was associated with reduced AMI risk (p = 0.015, OR = 0.46). CONCLUSIONS: Variation in the VEGF gene is weakly associated with IMT and the risk of AMI, but the effect can only be observed when the information of the SNPs is combined by constructing haplotypes.

Pneumonic tularaemia: experience of 58 cases from 2000 to 2012 in Northern Finland.

BACKGROUND: Pneumonic tularaemia is less common clinical form of tularaemia compared with the ulceroglandular form, with only a limited number of case reports and case series in Europe. In Finland, Northern Ostrobothnia is an endemic area of tularaemia with occasional seasonal outbreaks. METHODS: In our study, a consecutive series of 58 pneumonic tularaemia cases diagnosed and treated in Oulu University Hospital in 2000-2012 were retrospectively analysed in terms of epidemiology, clinical course, and prognosis. RESULTS: The incidence of pneumonic tularaemia showed peaks in cycles of a few years and most cases were diagnosed in late summer or early autumn. Respiratory symptoms were absent in 47% of patients, and 7% had normal chest X-ray. The chest computed tomography (CT) was performed in 81% of patients, demonstrating variable findings associated with pneumonic tularaemia. Bronchoscopy was performed for 22 (38%) patients and four (18%) of these also proceeded into mediastinoscopy. Moreover, thoracoscopy was performed for one (2%) patient. Two (3%) patients were treated shortly in the intensive care unit (ICU) during their stay in hospital. No mortality was observed. CONCLUSIONS: Most cases of pneumonic tularaemia are diagnosed during the seasonal outbreaks. The lack of specific symptoms often complicates the diagnosis and leads to unnecessarily invasive examinations.

Non-alcoholic fatty liver disease with and without metabolic syndrome: Different long-term outcomes.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are both shown to increase the risk of cardiovascular diseases and type 2 diabetes. However, there is a great overlap between these two diseases. The present study was aimed to examine the cardiovascular and metabolic prognosis of non-alcoholic fatty liver disease with and without metabolic syndrome. METHODS: Middle-aged subjects (n=958) were divided into four subgroups, those with NAFLD and MetS, those with NAFLD or MetS, and healthy controls. The baseline characteristics of the subgroups were analyzed. The follow-up time for cardiovascular events was about 16years. After approximately 21years the cardiac ultrasound and laboratory parameters were re-analyzed and new type 2 diabetes cases were recorded. RESULTS: Those with both diseases were at the greatest risk for cardiovascular events (p<0.001). Compared to healthy controls, only those with MetS, with or without NAFLD, were at increased risk for the development of type 2 diabetes (p<0.001) and for an increase in left ventricular mass index (p=0.001 and p=0.005, respectively). The cardiovascular and metabolic risk in subjects with NAFLD only was quite similar to that in healthy controls. The I148M variant of the patatin-like phospholipase domain-containing 3 gene (PNPLA3 polymorphism) was most present in those with NAFLD only (p=0.008). CONCLUSIONS: NAFLD with MetS implies a considerable risk for cardiovascular diseases, type 2 diabetes and the increase of left ventricular mass index whereas NAFLD without MetS does not.

Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology.

The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage.