Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglycosaminuria mice

Aspartylglycosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of glycosylasparaginase (AGA), and characterized by motor and mental retardation. Enzyme replacement therapy (ERT) in adult AGU mice with AGA removes the accumulating substance aspartylglucosamine from and reverses pathology in many somatic tissues, but has only limited efficacy in the brain tissue of the animals. In the current work, ERT of AGU mice was initiated at the age of 1 week with three different dosage schedules of recombinant glycosylasparaginase. The animals received either 3.4 U of AGA/kg every second day for 2 weeks (Group 1), 1.7 U/kg every second day for 9 days followed by an enzyme injection once a week for 4 weeks (Group 2) or 17 U/kg at the age of 7 and 9 days (Group 3). In the Group 1 and Group 3 mice, ERT reduced the amount of aspartylglucosamine by 34 and 41% in the brain tissue, respectively. No therapeutic effect was observed in the brain tissue of Group 2 mice. As in the case of adult AGU mice, the AGA therapy was much more effective in the somatic tissues than in the brain tissue of the newborn AGU mice. The combined evidence demonstrates that a high dose ERT with AGA in newborn AGU mice is up to twofold more effective in reducing the amount of the accumulated storage material from the brain tissue than ERT in adult AGU animals, indicating the importance of early detection and treatment of the disease.     

Blood transit time heterogeneity is associated to oxygen extraction in exercising human skeletal muscle

Capillary transit time and its heterogeneity have a marked impact on oxygen extraction in different tissues. Animal studies have shown that exercise shortens capillary transit time but the effects on capillary transit time heterogeneity have been controversial. We investigated whether exercise changes muscle blood transit time heterogeneity in humans in vivo and whether this heterogeneity correlates to muscle oxygen extraction. Muscle blood flow, blood volume, and oxygen uptake were measured during rest and low-intensity exercise in 12 healthy men using positron emission tomography (PET). Blood transit time was calculated from parametric PET images voxel by voxel by dividing blood volume with blood flow. Oxygen extraction was calculated by nonlinear fitting from dynamic 15O-O2 data. Relative dispersion (=SD/mean) was calculated as an index of heterogeneity of blood volume and blood transit time. As expected, exercise significantly shortened blood transit time and increased oxygen extraction. Furthermore, exercise decreased transit time heterogeneity (from 47 +/- 9% to 39 +/- 10%, P=0.07). Transit time heterogeneity correlated inversely to oxygen extraction in the exercising (r=-0.76, P=0.004) but not in the resting muscle (r=0.04, P=0.89). These results show that even low-intensity exercise shortens blood transit time markedly and decreases its heterogeneity in human skeletal muscle in vivo. Findings in correlation analyses suggest that less heterogeneous blood transit time associates to better muscle oxygen extraction during exercise. This may have effects on muscle oxygenation during exercise.     

Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers

Objective Tooth loss has been associated with upper gastrointestinal cancer in several studies, but only one previous study used prospectively collected data. The importance of confounding by Helicobacter pylori has not previously been addressed. The objective was to determine the association between tooth loss and upper gastrointestinal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort and to determine the importance of potentially confounding dietary factors or H. pylori seropositivity. Material and methods A prospective cohort study with 29,124 subjects included 49 esophageal squamous cell carcinomas, 66 esophageal/gastric cardia adenocarcinomas, and 179 gastric non-cardia adenocarcinomas occurring between 1985 and 1999. Cox proportional hazards models adjusted for age and education were used to estimate hazard ratios (HRs) and 95% CIs. Odds ratios and 95% CIs were calculated with and without adjustment for H. pylori seropositivity in a nested case-control group to determine whether H. pylori confounded the association between tooth loss and gastric cancer. Results Tooth loss significantly increased the hazard ratio for gastric non-cardia cancer, the HR (95% CI) for edentulous subjects versus those with <10 teeth lost was 1.65 (1.09, 2.49, respectively). No statistically significant associations were found between tooth loss and esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma. Confounding by dietary factors, tobacco smoking, or H. pylori did not explain these results. Conclusions Tooth loss was associated with increased risk of gastric non-cardia cancer, but not esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma in this Finnish cohort.     

Health-related quality of life in patients with common rheumatic diseases referred to a university clinic

The aim of the present study was to assess the health-related quality of life (HRQoL) in patients with common rheumatic diseases referred to a rheumatology clinic and to compare it to the HRQoL of the general population. All patients with a new referral to the Department of Rheumatology of the Helsinki University Central Hospital were asked to participate in the study during the period from May 2002 to April 2003. A total of 295 patients with various rheumatic diseases were included in the analysis: 99 patients with rheumatoid arthritis (RA), 47 with arthralgia and fibromyalgia, 43 with other chronic arthritis (spondyloarthritis, psoriatic arthritis, enteropathic arthritis), 44 with osteoarthritis (OA), 22 with active reactive arthritis (ReA), 17 with systemic rheumatic diseases, 9 adults with juvenile idiopathic arthritis (JIA) and 14 with other diagnoses. HRQoL was measured by a disease specific instrument, the Stanford health assessment questionnaire (HAQ) and by a generic instrument, 15D. The mean baseline 15D score of the 295 included patients (0.822, SD 0.114) was significantly lower than of the general population (0.903, SD 0.098). Patients with OA and chronic arthritis reported the poorest HRQoL scores (both 0.810 on a 0-1 scale). In patients with RA and ReA the 15D score improved in a statistically significant and clinically important manner during the 8-month follow-up. Discomfort and symptoms caused by the disease were alleviated in a statistically significant manner in patients with RA as well as in those with arthralgia and fibromyalgia, chronic arthritis, ReA and systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. The HRQoL of patients with common rheumatic diseases at referral to rheumatology clinic is significantly lower than the HRQoL of age-standardized general population. The most affected patients are those with OA, chronic arthritis and RA. A significant improvement in HRQoL with conventional interventions was achieved in patients with RA and ReA.     

The Pro12Ala polymorphism of the PPARγ2 gene is associated with hepatic glucose uptake during hyperinsulinemia in subjects with type 2 diabetes mellitus

The Ala12 allele of the peroxisome proliferator-activated receptor γ gene (PPARG2) has been associated with reduced risk of type 2 diabetes mellitus (T2DM) and increased whole-body and skeletal muscle insulin sensitivity in nondiabetic subjects. The effect of the Pro12Ala polymorphism on tissue specific insulin sensitivity in subjects with T2DM has not been previously investigated. We studied the effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake (GU) in T2DM subjects, and the rates of hepatic GU in nondiabetic and T2DM subjects during hyperinsulinemia. Our study included 105 T2DM subjects whose whole-body, skeletal muscle, subcutaneous adipose tissue, and hepatic GUs were measured using ¹⁸F-fluorodeoxyglucose and positron emission tomography during the hyperinsulinemic euglycemic clamp. Hepatic GU was also measured in 68 nondiabetic subjects. In obese (body mass index ≥27 kg/m²) subjects with T2DM, the rate of hepatic GU was 28% lower in subjects with the Pro12Pro genotype than in carriers of the Ala12 allele (P = .001); and a similar trend was observed in nondiabetic obese subjects (P = .137). No effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, or subcutaneous adipose tissue GU was observed in T2DM subjects. We conclude that the Ala12 allele of PPARG2 is associated with higher hepatic GU in obese subjects with T2DM.     

Folding without charges

Surface charges of proteins have in several cases been found to function as “structural gatekeepers,” which avoid unwanted interactions by negative design, for example, in the control of protein aggregation and binding. The question is then if side-chain charges, due to their desolvation penalties, play a corresponding role in protein folding by avoiding competing, misfolded traps? To find out, we removed all 32 side-chain charges from the 101-residue protein S6 from Thermus thermophilus. The results show that the charge-depleted S6 variant not only retains its native structure and cooperative folding transition, but folds also faster than the wild-type protein. In addition, charge removal unleashes pronounced aggregation on longer timescales. S6 provides thus an example where the bias toward native contacts of a naturally evolved protein sequence is independent of charges, and point at a fundamental difference in the codes for folding and intermolecular interaction: specificity in folding is governed primarily by hydrophobic packing and hydrogen bonding, whereas solubility and binding relies critically on the interplay of side-chain charges.     

An echocardiographic study of right and left ventricular adaptation to physical exercise in elite female orienteers.

BACKGROUND: A considerable body of echocardiographic studies has described how athletic training induces morphological adaptation of the left ventricle in male endurance athletes, but only a few studies have described left ventricular adaptation in female endurance athletes. In contrast to changes in the left ventricle far less attention has been directed towards right ventricular changes due to extensive physical exercise. The purpose of this study was to obtain normal values and to determine if there are any differences in right and left ventricular cavity and wall dimensions between female orienteers and females with a mainly sedentary lifestyle. METHODS: Echocardiography was performed in 42 highly trained elite female orienteers and 32 healthy female students with a predominantly sedentary lifestyle. The 74 females had no history of cardiac disease, a normal electrocardiogram and showed no echocardiographic abnormalities. M-mode and two-dimensional measurements of the right and left ventricular cavity and wall were obtained in elite orienteers and sedentary females. For the right ventricle and wall, multiple cross-sections were used and measurements were obtained from the right ventricular inflow and outflow tract. RESULTS: The left ventricular end-diastolic cavity dimension and the left ventricular wall thickness were significantly greater in the athletes compared with the sedentary controls. The right ventricular inflow tract measurements were all significantly greater in the orienteers compared with the controls but the right ventricular outflow tract measurements were comparable in the study groups. The right ventricular wall thickness, calculated as the mean of three different wall measurements was an average of 13% greater in the athletes compared with the sedentary controls. CONCLUSION: This study suggests symmetrical cardiac enlargement with a concomitant increase in both the right and left ventricular wall, probably reflecting the increased haemodynamic loading in the female athletes.     

An outbreak caused by the SARS-CoV-2 Delta variant (B.1.617.2) in a secondary care hospital in Finland,May 2021

An outbreak caused by the SARS-CoV-2 Delta variant (B.1.617.2) spread from one inpatient in a secondary care hospital to three primary care facilities, resulting in 58 infections including 18 deaths in patients and 45 infections in healthcare workers (HCW). Only one of the deceased cases was fully vaccinated. Transmission occurred despite the use of personal protective equipment by the HCW, as advised in national guidelines, and a high two-dose COVID-19 vaccination coverage among permanent staff members in the COVID-19 cohort ward.     

Cost-utility of molecular adsorbent recirculating system treatment in acute liver failure

AIM:To determine the short-term cost-utility of mo-lecular adsorbent recirculating system(MARS) treatment in acute liver failure(ALF).METHODS:A controlled retrospective study was conducted with 90 ALF patients treated with MARS from 2001 to 2005.Comparisons were made with a historical control group of 17 ALF patients treated from 2000 to 2001 in the same intensive care unit(ICU) specializing in liver diseases.The 3-year outcomes and number of liver transplantations were recorded.All direct liver disease-rel...     

Tolerability and Kinetics of a Solvent-Detergent-Treated Intravenous Immunoglobulin Preparation in Hypogammaglobulinaemia Patients

The tolerability and kinetics of a solvent-detergent-treated 6% intravenous immunoglobulin (IVIG) preparation were studied in 15 hypogammaglobulinaemia patients during 3–4 regular substitution infusions of 9–18 g, the mean dose being 359 mg/kg. The infusions were well tolerated, and the trough serum IgG levels achieved were comparable to two commercial IVIG preparations. The stepwise increase of the infusion rate up to 5 mg/kg/min and the use of this IVIG as a 12% solution were possible without serious adverse events in all the 6 studied hypogammaglobulinaemia patients. This greatly reduced the time needed for the infusions.