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Study aim: The purpose of this study was to evaluate neuromuscular adaptations in conscripts with different fitness levels (VO2max) during 8 weeks of military basic training (BT).

Study Objectives: Arousal burden (AB) is defined as the cumulative duration of arousals during sleep divided by the total sleep time. However, in-depth analysis of AB related to sleep characteristics is lacking. Based on previous studies addressing the arousal index (ArI), we hypothesized that the AB would peak in the supine sleeping position and during non-rapid eye movement stage 1 (N1) and show high variability between scorers., Methods: Nine expert scorers analyzed polysomnography recordings of 50 participants, the majority with an increased risk for obstructive sleep apnea. AB was calculated in different sleeping positions and sleep stages. A generalized estimating equation was utilized to test the association between AB and sleeping positions, sleep stages, and scorers. The correlation between AB and ArI was tested with Spearman's rank-order correlation., Results: AB significantly differed between sleeping positions ( p <0.001). The median AB in the supine sleeping position was 47-62% higher than in the left and right position. The AB significantly differed between the sleep stages ( p <0.001); the median AB was more than 200% higher during N1 than during other sleep stages. In addition, the AB differed significantly between scorers ( p <0.001) and correlated strongly with ArI ( r =0.935, p <0.001)., Conclusions: AB depends on the sleeping position, sleep stage, and scorer as hypothesized. AB behaved similarly as the ArI, but the high variability in the ABs between scorers indicates a potential limitation caused by subjective manual scoring. Thus, the development of more accurate techniques for scoring arousals is required before AB can be reliably utilized., (© 2024 American Academy of Sleep Medicine.)

Vitamin D analogue calcipotriol is currently used in the local treatment of psoriasis. However, it also has antiproliferative and anti-inflammatory effects in the cells of the joint - suggesting a possible benefit in local treatment of arthritis. In this study, calcipotriol was studied in different in vitro methods to find out its effect on synovial and mesenchymal stromal cells. Primary human cell lines of osteoarthritis or rheumatoid arthritis patients (five mesenchymal stromal cells, MSC, and four synovial stromal cells, SSC) were cultured to study migration and proliferation of the cells in a wound healing model. The media was supplemented with calcipotriol, 1,25(OH) 2 D 3 , dexamethasone, betamethasone, methylprednisolone or control solution in 1-100 nM concentrations. To see possible toxic effects of calcipotriol, concentrations up to 10 µM in SSCs and MSCs were studied in apoptosis and necrosis assays in four cell lines. Calcipotriol and 1,25(OH) 2 D 3 , as well as the three glucocorticoids, reduced the migration of both SSCs and MSCs. In SSCs, the effect of calcipotriol and 1,25(OH) 2 D 3 was at least as effective as with glucocorticoids, while with MSCs, the glucocorticoids were stronger inhibitors of migration. The antimigratory of calcipotriol and 1,25(OH) 2 D 3 was consistently maintained in 10 µM and 1 µM. Calcipotriol was not toxic to MSCs and SSCs up to concentrations of 10 µM. Calcipotriol, as well as 1,25(OH) 2 D 3 , exerts antimigratory and antiproliferative effects on human SSCs and MSCs of the joint. These effects are not caused by apoptosis or necrosis. Both calcipotriol and 1,25(OH) 2 D 3 have similar effects as glucocorticoids without apparent toxicity, suggesting that calcipotriol might be an eligible candidate to the local treatment of arthritis with a broad therapeutic window., Competing Interests: Declarations of interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Calcipotriol, a vitamin D analogue, is an antiproliferative and anti-inflammatory drug currently used in psoriasis. Here, our aim was to analyse the safety of calcipotriol for cartilage and bone in alleviated-dose (0.1 mg instead of usual ≥1mg dose) zymosan-induced arthritis in rats. Theoretically, high doses of vitamin D or analogues could have detrimental effects on bone or cartilage. The rats were divided into four groups: vehicle (n = 9), dexamethasone 0.1 mg/kg (n = 9), calcipotriol 0.1 mg/kg (n = 8) and negative control (n = 10) with no injections. Arthritic rats were given phosphate-buffered saline (PBS) injections to left knees as a control. After euthanasia on day 8, all knees were imaged with micro-computed tomography for surface lesions and decalcified for histological analyses. Contrary to our expectations, no significant changes could be observed in the tomography data and histological scores among the three treatment groups or between the vehicle-treated and non-arthritic group. Calcipotriol did not cause adverse effects on cartilage or subchondral bone within a week, suggesting that it could be safely used in local treatment of arthritis. The alleviated model caused synovitis with local and systemic inflammatory response without cartilage erosions, which might be useful in studying self-limiting synovitis where cartilage or bone effects are not of primary interest., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

1,25-dihydroxyvitamin-D3 and its derivatives have shown anti-arthritic and chondroprotective effects in experimental animal models with prophylactic dosing. The purpose of this preliminary study was to test the efficacy and safety of calcipotriol, vitamin D analog, as a treatment for a fully-developed knee arthritis in Zymosan-induced arthritis (ZIA) model. Forty 5-month-old male Sprague-Dawley rats were randomized into three arthritis groups and a non-arthritic control group with no injections (10 rats/group). A day after Zymosan (0.1 mg) had been administrated into the right knee joints, the same knees were injected with calcipotriol (0.1 mg/kg), dexamethasone (0.1 mg/kg) or vehicle in a 100 μl volume. The left control knees were injected with saline (PBS) on two consecutive days. All injections, blood sampling and measurements were performed under general anesthesia on days 0, 1, 3 and 8. Internal organs and knees were harvested on day 8 and the histology of the whole knees was assessed blinded. Joints treated with calcipotriol showed a milder histological synovitis than those treated with vehicle (p = 0.041), but there was no statistically significant difference between the dexamethasone and vehicle groups. The clinical severity of arthritis did not differ between the arthritis groups measured by body temperature, swelling of the knee, thermal imaging, clinical scoring or cytokine levels on days 1, 3 and 8. Weight loss was bigger in rats treated with dexamethasone, propably due to loss of appetite,compared to other arthritis groups on days 2-3 (p<0.05). Study drugs did not influence serum calcium ion and glucose levels. Taken together, this preliminary study shows that a single intra-articular injection of calcipotriol reduces histological grade of synovitis a week after the local injection, but dexamethasone did not differ from the vehicle. Calcipotriol may have an early disease-modifying effect in the rat ZIA model without obvious side effects., Competing Interests: The authors have declared that no competing interests exist.

Background: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families., Methods: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann-Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses., Results: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1-12.9, p = 0.030)., Conclusions: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.

Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.1 mg/kg given to one sheep) and intra-articular dose (0.054 mg/kg, 0.216 mg/kg and 0.560 mg/kg given to three sheep). The terminal half-life of calcipotriol was approximately 1 h after an IV dose. After intra-articular dosing, the systemic absorption was between 1 and 13% during the observed 24 h. Hypercalcemia or other clinical adverse effects did not occur in any animal during the study, and no macroscopic or microscopic alterations were seen in the synovium of the calcipotriol-injected knees compared to the vehicle knees. The in vitro metabolism of calcipotriol was analyzed with LC-MS from human synovial and mesenchymal stromal cell cultures. Both cell types were able to metabolize calcipotriol with MC1080 and MC1046 as the main metabolites. CYP24A1 transcripts were strongly induced by a 48-hour calcipotriol exposure in mesenchymal stromal cells, but not consistently in synovial stromal cells, as determined by RT-qPCR. Calcipotriol proved to be safe after a single intra-articular dose with applied concentrations, and it is metabolized by the cells of the joint. Slow dissolution of calcipotriol crystals in the joint can extend the pharmaceutical impact on the synovium, cartilage and subcortical bone., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Military training loads may induce different physiological responses in garrison and field training and only a little is known about how short-time recovery, lasting a few days, affects neuromuscular fitness and hormonal profile. This study aimed to investigate the effects of garrison and field military service on neuromuscular performance and hormonal profile and to evaluate the effects of a 3-day recovery on those factors., Methods: Twenty healthy male soldiers (20 ± 1 years) participated in the study, which consisted of 4 days of garrison training [days (D) 1-4] and 7 days of military field training (Days 5-12) followed by a 3-day recovery period (Day 15). Serum hormone concentrations [testosterone (TES), cortisol (COR), sex-hormone binding globulin (SHBG), free thyroxine (T4)] were assessed at D1, D5, D8-12, and D15. Handgrip strength was measured in 10 participants at D1, D5, D8, D12, and D15. Maximal isometric force, electromyography, and rate of force development (RFD) of the knee extensors and arm flexors were also measured at D5, D12, and D15., Results: The maximal force of both the arm flexors and knee extensors was not affected by the garrison or field training, whereas the RFD of the knee extensors was decreased during the field training (D5: 383 ± 130 vs. D12: 321 ± 120 N/s, p < 0.05). In addition, handgrip strength was mostly no affected, although a significant difference was observed between D8 and D12 (531 ± 53 vs. 507 ± 43 N, p < 0.05) during the field training. TES decreased already during the garrison training (D1: 18.2 ± 3.9 vs. D5: 16.2 ± 4.0 nmol/L, p < 0.05) and decreased further during the field training compared to baseline (D8: 10.2 ± 3.6 - D11: 11.4 ± 5.4 nmol/L, p < 0.05) exceeding the lowest concentration in the end of the field training (D12: 7.1 ± 4.1 nmol/L, p < 0.05). Similar changes were observed in free TES (D1: 72.2 ± 31.4 vs. D12: 35.1 ± 21.5 nmol/L, p < 0.001). The TES concentration recovered back to the baseline level and free TES increased after the recovery period compared with the baseline values (D15: 19.9 ± 5.3 nmol/L, D15: 99.7 ± 41.1 nmol/L, respectively). No changes were observed in the COR or SHBG concentrations during the garrison period. COR was decreased in the end of the field training (D12: 388 ± 109 nmol/L) compared with baseline (D1: 536 ± 113 nmol/L) (p < 0.05-0.001) but recovered back to the baseline levels after the recovery period (D15: 495 ± 58 nmol/L), whereas SHBG linearly increased towards the end of the field training (p < 0.05-0.001)., Conclusions: The present findings demonstrate that neuromuscular performance can be relatively well maintained during short-term garrison and field training even when a clear decrease in hormonal profile is evident. In addition, hormonal responses during field training seem to be greater compared to garrison training, however, the recovery of 3-day in free-living conditions seems to be sufficient for hormonal recovery. Therefore, a short-term recovery period lasting few days after the military field training may be required to maintain operational readiness after the field training., (© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects., Objective: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients., Methods: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition., Results: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition., Conclusion: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH., Objective: We aim to evaluate the role of AD-related polymorphisms in iNPH., Methods: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208&#95;A, rs2446581&#95;A, rs17314229&#95;T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA&#95;DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis., Results: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD., Conclusions: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE ε4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis., Objective: To investigate the individual and combined risk effects of the newly identified AD loci., Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex., Results: Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction., Conclusions: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

The purpose was (a) to study the effect of an 8-week Finnish military basic training period (BT) on physical fitness, body composition, mood state, and serum biochemical parameters among new conscripts; (b) to determine the incidence of overreaching (OR); and (c) to evaluate whether initial levels or training responses differ between OR and noOR subjects. Fifty-seven males (19.7 ± 0.3 years) were evaluated before and during BT. Overreaching subjects had to fulfill 3 of 5 criteria: decreased aerobic physical fitness (VO2max), increased rating of perceived exertion (RPE) in 45-minute submaximal test at 70% of VO2max or sick absence from these tests, increased somatic or emotional symptoms of OR, and high incidence of sick absence from daily service. VO2max improved during the first 4 weeks of BT. During the second half of BT, a stagnation of increase in VO2max was observed, basal serum sex hormone-binding globulin (SHBG) increased, and insulin-like growth factor-1 and cortisol decreased. Furthermore, submaximal exercise-induced increases in cortisol, maximum heart rate, and postexercise increase in blood lactate were blunted. Of 57 subjects, 33% were classified as OR. They had higher basal SHBG before and after 4 and 7 weeks of training and higher basal serum cortisol at the end of BT than noOR subjects. In addition, in contrast to noOR, OR subjects exhibited no increase in basal testosterone/cortisol ratio but a decrease in maximal La/RPE ratio during BT. As one-third of the conscripts were overreached, training after BT should involve recovery training to prevent overtraining syndrome from developing. The results confirm that serum SHBG, cortisol, and testosterone/cortisol and maximal La/RPE ratios could be useful tools to indicate whether training is too strenuous.

Finland is the only Nordic country with a nationwide system of quality control of the activities of the clinical laboratories, which covers both specialized and primary medical care. Practical experience of this quality control is reported. In empirical terms the organization functions well and the level attained by the health centre laboratories matches that of those at the central hospitals. Thus tests performed on patients at the health centres need not be repeated in hospital by reason of inferior quality.