Adenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX brain PET study

In this study, positron emission tomography (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)—a potent regulator of inflammation—was used to gain insight into the molecular alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional mangnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [¹¹C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution volumes (V_T) of [¹¹C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [¹¹C]TMSX-V_T in NAWM compared with controls (mean (s.d.): 0.55 (±0.08) vs. 0.45 (±0.05); P=0.036). Both the increased V_T and the decreased fractional anisotropy (FA) in NAWM were associated with higher expanded disability status scale (EDSS) scores (P=0.030 and P=0.012, respectively), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [¹¹C]TMSX-PET provides a novel approach to learn about central nervous system pathology in SPMS in vivo.     

A population based study of outcomes after evacuation of primary supratentorial intracerebral hemorrhage

Background and Purpose

The role of surgery after primary intracerebral hemorrhage (ICH) is controversial. To explore whether hematoma evacuation after ICH had improved short-term survival or functional outcome we conducted a retrospective observational population-based study.

Methods

We identified all subjects with primary ICH between 1993 and 2008 among the population of Northern Ostrobothnia, Finland. Hematoma evacuation was carried out by using standard craniotomy or through a burr hole. We compared mortality rates and functional outcomes of patients with hematoma evacuation with those treated conservatively.

Results

Of 982 patients with verified ICH during the study period, 127 (13%) underwent hematoma evacuation. Surgically treated patients were significantly younger (mean ± SD, 63 ± 11 vs. 70 ± 12 years; p < 0.001), had larger hematomas (66 ± 36 vs. 28 ± 40 ml; p < 0.001), lower Glasgow Coma Scale scores (median, 11 vs. 14; p < 0.001) and more frequently subcortical hematomas (68% vs. 24%; p < 0.001) than those treated conservatively. In multivariable analysis, hematoma evacuation independently lowered 3-month mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.43–0.88; p < 0.03), particularly among patients aged ≤70 years with ≥30 ml supratentorial hematomas (adjusted HR, 0.26; 95% CI, 0.14–0.49; p < 0.001). However, poor outcome was not improved by surgery (adjusted odds ratio 0.71; 95% CI 0.29–1.70).

Conclusions

Improved 3-month survival was observed in patients who had undergone hematoma evacuation relative to patients not undergoing evacuation particularly in the subgroup of patients aged ≤70 years with ≥30 ml supratentorial hematomas. Surgery might improve outcome if cases could be selected more precisely and if performed before deterioration.     

Temperament profiles in personality disorders among a young adult population

The objective of this study was to describe the temperament dimension profiles assessed by the Temperament and Character Inventory (TCI) among young adults with the DSM-III-R personality disorder (PD). Our hypothesis was that PD clusters and separate PDs can be distinguished from one another by their specific temperament profiles. As a part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort, the cohort members living in the city of Oulu at the age of 31 years (n=1609) were invited to participate in a two-phase field study. The Structured Clinical Interview for DSM-III-R for PDs (SCID–II) was used as diagnostic instrument. The final study sample consisted of the 1311 subjects who had completed the Hopkins Symptom Check List-25 questionnaire for screening and had given a written informed consent. Of the 321 SCID interviewed subjects, 74 met the criteria for at least one PD and had completed the TCI. The mean TCI scores of subjects with PD and control subjects without PD (n=910) were compared. Low Novelty Seeking, high Harm Avoidance and low Reward Dependence characterized cluster A and C PDs. Subjects with a cluster B PD did not differ from controls, except for Novelty Seeking, which was high. The temperament dimensions could not distinguish different PDs very well, with the only exception of persons with obsessive–compulsive PD. PD clusters were associated with different profiles of temperament, lending some support for Cloninger's typology.     

Surgery for stress urinary incontinence in Finland 1987–2009

Introduction and hypothesis

To estimate the incidence rates of stress urinary incontinence (SUI) surgery among Finnish women from 1987 to 2009 by age, and to evaluate the trends in SUI surgery.

Methods

We conducted a retrospective register-based study. All SUI procedures on adult women over age 18 years in Finland were identified from the nationwide Care Register for Health Care. Age-specific incidence rates per 1,000 women were calculated for each year. The cumulative incidence of SUI surgery was calculated.

Results

There were 38,340 procedures for SUI in 1987–2009. The overall age-adjusted incidence rate increased 2.6-fold from 0.5/1,000 women in 1987 to 1.3/1,000 in 2002, but declined thereafter by 2009 to 0.8/1,000. There was a six-fold increase in the incidence rate in the age group 60–69 years and a ten-fold increase in the age group 70–79 years from 1987 to 2002. These marked increases in operation rates coincided with the increased use of tension-free vaginal tape (TVT). In 2002, TVT accounted for 96 % of all SUI procedures. Mid-urethral slings with transobturator techniques surpassed TVT in popularity in 2007. The life-long cumulative incidence of SUI surgery was 9.9 % in 2002 and 6.3 % in 2009.

Conclusions

The incidence rates of SUI surgery increased significantly in Finland, especially among women aged 60 to 79 years. Mid-urethral slings have become the dominant procedure.

     

Optical spectroscopic determination of human meniscus composition

This study investigates the correlation between the composition of human meniscus and its absorption spectrum in the visible (VIS) and near infrared (NIR) spectral range. Meniscus samples (n = 24) were obtained from nonarthritic knees of human cadavers with no history of joint diseases. Specimens (n = 72) were obtained from three distinct sections of the meniscus, namely; anterior, center, posterior. Absorption spectra were acquired from each specimen in the VIS and NIR spectral range (400–1,100 nm). Following spectroscopic probing, the specimens were subjected to biochemical analyses to determine the matrix composition, that is water, hydroxyproline, and uronic acid contents. Multivariate analytical techniques, including principal component analysis (PCA) and partial least squares (PLS) regression, were then used to investigate the correlation between the matrix composition and it spectral response. Our results indicate that the optical absorption of meniscus matrix is related to its composition, and this relationship is optimal in the NIR spectral range (750–1,100 nm). High correlations (R²_uronic = 86.9%, R²_water = 83.8%, R²_{hydroxyproline} = 81.7%, p < 0.0001) were obtained between the spectral predicted and measured meniscus composition, thus suggesting that spectral data in the NIR range can be utilized for estimating the matrix composition of human meniscus. In conclusion, optical spectroscopy, particularly in the NIR spectral range, is a potential method for evaluating the composition of human meniscus. This presents a promising technique for rapid and nondestructive evaluation of meniscus integrity in real‐time during arthroscopic surgery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:270–278, 2016.     

Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

Key points

• Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents.
• Little is known about the effects of high‐intensity interval training (HIT) or of purely anaerobic resistance training on AHN.
• Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats.
• We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity.
• Our results confirm that sustained aerobic exercise is key in improving AHN.

Abstract

Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high‐intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low‐response trainer (LRT) and high‐response trainer (HRT) adult male rats to various forms of physical exercise for 6–8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin‐positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non‐significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength. Furthermore, RT had no effect on proliferation (Ki67), maturation (doublecortin) or survival (bromodeoxyuridine) of new adult‐born hippocampal neurons in adult male Sprague–Dawley rats. Our results suggest that physical exercise promotes AHN most effectively if the exercise is aerobic and sustained, especially when accompanied by a heightened genetic predisposition for response to physical exercise.

Abbreviations

AHN

adult hippocampal neurogenesis

BDNF

brain‐derived neurotrophic factor

BrdU

bromodeoxyuridine

HIT

high‐intensity interval training

HRT

high‐response trainer

LRT

low‐response trainer

RW

running wheel

Sed

sedentary

TBS

Tris‐buffered saline

V˙O2max

maximal oxygen uptake

     

Human articular cartilage proteoglycans are not undersulfated in osteoarthritis

Chondroitin sulfate is the major constituent of cartilage. Inadequate sulfate availability results in the production of undersulfated proteoglycans. In osteoarthritis, there is a net loss of articular cartilage proteoglycans. Theoretically, it is possible that during the progress of disease undersulfated glycosaminoglycans are synthesized producing proteoglycans with poorer biological properties. In this study, we tested whether in early human osteoarthritic articular cartilage (Mankin's score of 2 and 3) or more advanced disease (Mankin's score over 3), there are proteoglycans that contain a higher relative amount of nonsulfated chondroitin disaccharide isomer in their chondroitin sulfate chains by analyzing the molar ratios of chondroitin sulfate disaccharide isoforms with fluorophore-assisted carbohydrate electrophoresis. Our results indicated that the nonsulfated disaccharide of chondroitin sulfate formed in average only 1-2% of the total chondroitin sulfate. More important, the molar ratio of nonsulfated disaccharide did not appear to be increased in the osteoarthritic articular cartilage. We conclude that undersulfation of articular cartilage proteoglycans is not present in the human osteoarthritic joint.     

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.     

Dual contrast in computed tomography allows earlier characterization of articular cartilage over single contrast

Cationic computed tomography contrast agents are more sensitive for detecting cartilage degeneration than anionic or non-ionic agents. However, osteoarthritis-related loss of proteoglycans and increase in water content contrarily affect the diffusion of cationic contrast agents, limiting their sensitivity. The quantitative dual-energy computed tomography technique allows the simultaneous determination of the partitions of iodine-based cationic (CA4+) and gadolinium-based non-ionic (gadoteridol) agents in cartilage at diffusion equilibrium. Normalizing the cationic agent partition at diffusion equilibrium with that of the non-ionic agent improves diagnostic sensitivity. We hypothesize that this sensitivity improvement is also prominent during early diffusion time points and that the technique is applicable during contrast agent diffusion. To investigate the validity of this hypothesis, osteochondral plugs (d = 8 mm, N = 33), extracted from human cadaver (n = 4) knee joints, were immersed in a contrast agent bath (a mixture of CA4+ and gadoteridol) and imaged using the technique at multiple time points until diffusion equilibrium. Biomechanical testing and histological analysis were conducted for reference. Quantitative dual-energy computed tomography technique enabled earlier determination of cartilage proteoglycan content over single contrast. The correlation coefficient between human articular cartilage proteoglycan content and CA4+ partition increased with the contrast agent diffusion time. Gadoteridol normalized CA4+ partition correlated significantly (P < .05) with Mankin score at all time points and with proteoglycan content after 4 hours. The technique is applicable during diffusion, and normalization with gadoteridol partition improves the sensitivity of the CA4+ contrast agent.