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Background: Musculoskeletal (MSK) disorders represent a significant burden to society and can be unpleasant for the affected individuals. Physical activity (PA) can prevent MSK disorders while conferring other health benefits. The present study aimed to investigate associations between device-measured PA and perceived MSK disorders among young adult men., Methods: PA at different intensity levels, standing, and sedentary behavior were measured with a hip-worn accelerometer in a cohort of 422 young adult Finnish men aged 26 years on average. The incidences of three common MSK disorders (viz., knee pain, lumbar radicular pain, and lumbago pain) during the last month were inquired by a questionnaire. Binary logistic regression was used to examine the associations between the MSK outcomes and explanatory PA variables (PA times at different intensity levels, standing, and sedentary times). The models were controlled for age, education, smoking, BMI, and maximal oxygen uptake., Results: PA, standing, and sedentary times were not significantly associated with the incidence of perceived MSK pain during the last month, except for lumbago pain. Lumbago pain was slightly more probable if the time spent in light PA increased, even after controlling for potential confounding factors, including moderate-to-vigorous PA, with an odds ratio (OR) of 1.07 (95% CI: 1.02-1.14). Sedentary time showed an opposite association, with an OR of 0.98 (95% CI: 0.96-1.00)., Conclusions: There were neither positive nor negative clinically meaningful associations between PA and recent MSK disorders among young adult men. The result is surprising and requires further confirmation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Sipilä, Sievänen, Raitanen, Kyröläinen, Vasankari, Vaara and Honkanen.)

Background: The recently described navigator proteins have a multifaceted role in cytoskeletal dynamics. We report here on the relevance of one of them, navigator 3 (NAV3), in colorectal cancer (CRC)., Methods: We analysed changes in chromosome 12 and NAV3 copy number in CRC/adenoma samples of 59 patients and in 6 CRC cell lines, using fluorescence in situ hybridisation, loss of heterozygosity, and array-CGH. NAV3 target genes were identified by siRNA depletion, expression arrays, and immunohistochemistry., Results: NAV3 deletion and chromosome 12 polysomy were detected in 30 and 70% of microsatellite stability (MSS) carcinomas, in 23 and 30% of adenomas and in four of six CRC cell lines. NAV3 amplification was found in 25% of MSS samples. NAV3 alterations correlated with lymph node metastasis. In normal colon cells, NAV3 silencing induced upregulation of interleukin 23 receptor (IL23R) and gonadotropin releasing hormone receptor. In MSS and microsatellite instability tumours, IL23R immunoreactivity correlated with Dukes' staging and lymph node metastases, whereas nuclear beta-catenin correlated with lymph node metastases only., Conclusion: NAV3 copy number changes are frequent in CRC and in adenomas, and upregulation of IL23R, following NAV3 silencing, strongly correlates with Dukes' staging and lymph node metastases. This suggests that NAV3 has a role in linking tissue inflammation to cancer development in the colon.

Bexarotene (Targretin(®)), was registered for the treatment of cutaneous T-cell lymphoma (CTCL) in 2002, and has been reported to induce a 45% overall response. Responses are mostly partial or generate a stable, skin-restricted disease. This study explored the usefulness of a novel cancer-associated gene, NAV3 and corresponding chromosome 12 copy numbers as possible biomarkers to monitor the therapeutic response to bexarotene in 21 Finnish patients with CTCL. Six patients (29%) reached complete remission (CR) and 3 of these remained in CR for more than 24 months, 12 (57%) reached a partial response (PR, with one stable disease) and 3 were non-responders. Low-level NAV3 deletions were detected using a fluorescence in-situ hybridization (FISH) assay in the lesions of 5 patients, 4 of whom were non-responders or progressed after short PR. This occurrence of NAV3 deletions was statistically significant compared with non-progressors (p = 0.011, Fisher's exact test). Chromosome 12 tetraploidy was found in the lesions of two of the 3 patients with CR who remained in remission. While such tetraploidy is a feature of proliferating normal T cells, this observation may reflect a favourable anti-tumour immune response among the skin-infiltrating lymphocytes.

Nine broadcast journalism students attended 10 hours in Kuukka vocal exercises, which aims at producing a ringing vocal quality. Nine control subjects received no training. A text was read at habitual loudness before and after the course. Five speech specialists evaluated the text samples for perceptual voice quality and analyzed mean fundamental frequency (F0), equivalent sound level (Leq), and long-term average spectrum (LTAS). For the Training Group, voice quality improved and correlated negatively with firmness and timbre (less firm and darker qualities being considered more desirable), and F0 increased slightly. Leq increased significantly in both groups. The results show positive and perceivable differences after the course. However, the aimed ring was not reached, may be due to too short time.

Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase, collagen galactosyltransferase, and glucosyltransferase (GGT) activities. We report here an important role for LH3 in the organization of the extracellular matrix (ECM) and cytoskeleton. Deposition of ECM was affected in heterozygous LH3 knock-out mouse embryonic fibroblasts (MEF(+/-)) and in skin fibroblasts collected from a member of a Finnish epidermolysis bullosa simplex (EBS) family known to be deficient in GGT activity. We show the GGT deficiency to be due to a transcriptional defect in one LH3 allele. The ECM abnormalities also lead to defects in the arrangement of the cytoskeleton in both cell lines. Ultrastructural abnormalities were observed in the skin of heterozygous LH3 knock-out mice indicating that even a moderate decrease in LH3 has deleterious consequences in vivo. The LH3 null allele in the EBS family member and the resulting abnormalities in the organization of the extracellular matrix, similar to those found in MEF(+/-), may explain the correlation between the severity of the phenotype and the decrease in GGT activity reported in this family.

Most lysines in type IV and VI collagens are hydroxylated and glycosylated, but the functions of these unique galactosylhydroxylysyl and glucosylgalactosylhydroxylysyl residues are poorly understood. The formation of glycosylated hydroxylysines is catalyzed by multifunctional lysyl hydroxylase 3 (LH3) in vivo, and we have used LH3-manipulated mice and cells as models to study the function of these carbohydrates. These hydroxylysine-linked carbohydrates were shown recently to be indispensable for the formation of basement membranes (Ruotsalainen, H., Sipilä, L., Vapola, M., Sormunen, R., Salo, A. M., Uitto, L., Mercer, D. K., Robins, S. P., Risteli, M., Aszodi, A., Fässler, R., and Myllylä, R. (2006) J. Cell Sci. 119, 625-635). Analysis of LH3 knock-out embryos and cells in this work indicated that loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens. Mice lacking the LH activity of LH3 produced slightly underglycosylated type IV and VI collagens with abnormal distribution. The altered distribution and aggregation of type VI collagen led to similar ultrastructural alterations in muscle to those detected in collagen VI knockout and some Ullrich congenital muscular dystrophy patients. Our results provide new information about the function of hydroxylysine-linked carbohydrates of collagens, indicating that they play an important role in the secretion, assembly, and distribution of highly glycosylated collagen types.

Hydroxylysine and its glycosylated forms, galactosylhydroxylysine and glucosylgalactosylhydroxylysine, are post-translational modifications unique to collagenous sequences. They are found in collagens and in many proteins having a collagenous domain in their structure. Since the last published reviews, significant new data have accumulated regarding these modifications. One of the lysyl hydroxylase isoforms, lysyl hydroxylase 3 (LH3), has been shown to possess three catalytic activities required sequentially to produce hydroxylysine and its glycosylated forms, that is, the lysyl hydroxylase (LH), galactosyltransferase (GT), and glucosyltransferase (GGT) activities. Studies on mouse models have revealed the importance of these different activities of LH3 in vivo. LH3 is the main molecule responsible for GGT activity in mouse embryos. A lack of this activity causes intracellular accumulation of type IV collagen, which disrupts the formation of basement membranes (BMs) during mouse embryogenesis and leads to embryonic lethality. The specific inactivation of the LH activity of LH3 causes minor alterations in the structure of the BM and collagen fibril organization, but does not affect the lifespan of mutated mice. Recent data from zebrafish demonstrate that growth cone migration depends critically on the LH3 glycosyltransferase domain. LH3 is located in the ER loosely associated with the membranes, but, unlike the other isoforms, LH3 is also found in the extracellular space in some tissues. LH3 is able to adjust the amount of hydroxylysine and hydroxylysine-linked carbohydrates of extracellular proteins in their native conformation, suggesting that it may have a role in matrix remodeling.

Lysyl hydroxylase catalyzes the hydroxylation of lysine residues in collagenous sequences. Three isoforms (LH1, LH2 and LH3) of lysyl hydroxylase have been characterized, and LH2 is present as two alternatively spliced forms. In order to better understand the functional differences between the isoforms in vivo, the expression of the different isoforms was studied in mouse embryos and adult tissues. Our data indicate a widespread expression of all isoforms during embryogenesis, whereas the expression profiles become more specialized in adult tissues. The expression of LH2 was more tissue-specific, whereas a uniform and housekeeping like behavior was observed for LH3. Some cells express both LH2 and LH3, while a clear cell specificity was seen in some tissues. Moreover, immunoelectron microscopy revealed differences in the localization of LH2 and LH3. LH2 was localized intracellularly in the ER in all tissues studied, whereas the localization of LH3 was either intracellular or extracellular or both, depending on the tissue. Furthermore, our data indicate that the alternative splicing of LH2 is developmentally regulated. The short form of LH2 (LH2a) is the predominant form until E11.5; the long form (LH2b) dominates thereafter and is the major form in many adult tissues. Interestingly, however, adult mouse kidney and testis express exclusively the short form, LH2a. The results reveal a specific regulation for the expression of LH isoforms as well as for alternative splicing of LH2 during embryogenesis and in different tissues.

Lysyl hydroxylase 3 (LH3), the multifunctional enzyme associated with collagen biosynthesis that possesses lysyl hydroxylase and collagen glycosyltransferase activities, has been characterized in the extracellular space in this study. Lysine modifications are known to occur in the endoplasmic reticulum (ER) prior to collagen triple-helix formation, but in this study we show that LH3 is also present and active in the extracellular space. Studies with in vitro cultured cells indicate that LH3, in addition to being an ER resident, is secreted from the cells and is found both in the medium and on the cell surface associated with collagens or other proteins with collagenous sequences. Furthermore, in vivo, LH3 is present in serum. LH3 protein levels correlate with the galactosylhydroxylysine glucosyltransferase (GGT) activity of mouse tissues. This, together with other data, indicates that LH3 is responsible for GGT activity in the tissues and that GGT activity assays can be used to quantify LH3 in tissues. LH3 in vivo is located in two compartments, in the ER and in the extracellular space, and the partitioning varies with tissue type. In mouse kidney the enzyme is located mainly intracellularly, whereas in mouse liver it is located solely in the extracellular space. The extracellular localization and the ability of LH3 to modify lysyl residues of extracellular proteins in their native, nondenaturated conformation reveals a new dynamic in extracellular matrix remodeling, suggesting a novel mechanism for adjusting the amount of hydroxylysine and hydroxylysine-linked carbohydrates in collagenous proteins., (Copyright 2006 Wiley-Liss, Inc.)

Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase (LH), hydroxylysyl galactosyltransferase (GT) and galactosylhydroxylysyl glucosyltransferase (GGT) activities in vitro. To investigate the in vivo importance of LH3-catalyzed lysine hydroxylation and hydroxylysine-linked glycosylations, three different LH3-manipulated mouse lines were generated. Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung. Analysis of a hypomorphic LH3 mouse line with the same mutation, however, demonstrated that the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5. Strikingly, survival of hypomorphic embryos and the formation of the basement membrane were directly correlated with the level of GGT activity. In addition, an LH3-knockout mouse lacked GGT activity leading to lethality at E9.5. The results confirm that LH3 has LH and GGT activities in vivo, LH3 is the main molecule responsible for GGT activity and that the GGT activity, not the LH activity of LH3, is essential for the formation of the basement membrane. Together our results demonstrate for the first time the importance of hydroxylysine-linked glycosylation for collagens.

Lysyl hydroxylase is an enzyme involved in collagen biosynthesis, catalyzing the hydroxylation of lysyl residues as a post-translational event. Three isoforms have been characterized so far (LH1, LH2, LH3). Our recent findings indicate that LH3 possesses, not only lysyl hydroxylase activity, but also galactosylhydroxylysyl glucosyltransferase activity [Heikkinen et al., J. Biol. Chem. 275 (2000) 36158-36163]. We report here the characterization of mouse LH2 (Plod2) and LH3/glucosyltransferase (Plod3) genes. Plod2 spans approximately 50 kb of the genomic DNA, and is organized in 20 exons, one of the exons being alternatively spliced in the RNA processing. Plod3 spans approximately 10 kb of the genomic DNA, and contains 19 exons. Analysis of the 5' flanking region with many transcription start sites reveals the lack of a TATAA box in both genes. Sequence analysis indicated many retroposon-like elements within the Plod3 gene. A comparison was carried out among the LH1, LH2 and LH3 gene structures characterized so far from different species.

We report on the isolation and characterization of cDNA clones for mouse lysyl hydroxylases 1, 2 and 3 (LH1, LH2, LH3). Phylogenetic analysis using nine lysyl hydroxylase sequences from five species indicates that the isoforms are derived from an ancestral gene by two duplication events, isoforms 1 and 2 being more closely related and having resulted from a more recent duplication than isoform 3. Expression of the isoforms is highly regulated in adult mouse tissues. LH1 is strongly expressed in the liver, heart, lung, skeletal muscle and kidney tissue, LH2 expression is high in the heart, lung, kidney, eye, ovary and placenta, whereas LH3 expression is high in the heart, lung, liver and testis tissue.

In this 8-year-old boy, who had been exposed to alcohol and oxazepam during pregnancy, visual failure was the first symptom of a neuronal ceroid lipofuscinosis (NCL) disorder, noticed at the age of 5 years. Ophthalmological examinations revealed a cystic type of macular degeneration, which would be more likely to be found in variant late infantile NCL. However, vacuolated lymphocytes were found in peripheral blood films and a diagnosis of the juvenile form of NCL (JNCL) was made. Molecular genetic studies showed the patient to be homozygous for the major mutation of JNCL, a 1.02-kb deletion. In whole-night polysomnography, there was significantly more epileptiform activity than in other JNCL patients under 10 years of age. Using magnetic resonance imaging, the signal intensity of the white matter was increased, especially in the periventricular area. In addition, there were enlarged perivascular spaces in the watershead areas. The corpus callosum was thin. Finally, in the autonomic ganglion cells of the submucosal nerve plexus there were membrane-enclosed homogeneous and granular cytosomes resembling the granular osmiophilic deposits of infantile NCL. However, extraneural cells, including blood capillaries and smooth muscle, showed inclusions with fingerprint and curvilinear profiles. The features of the present case indicated a phenotypic variant of JNCL.

Imaging parameters were optimized at 0.1 T to improve contrast-to-noise ratios (CNR) when combining magnetization transfer (MT) imaging and the use of paramagnetic contrast medium. This was accomplished by imaging a phantom containing serial concentrations of Gd-DTPA in cross-linked bovine serum albumin. With the use of simulations, the dependence of CNR on imaging parameters was studied. Conventional and MT images were obtained from 10 brain tumor patients with single and triple doses of Gd-DTPA. Simulations demonstrated the importance of TR in postcontrast sequences. The CNR in MT images is less sensitive to TR than in conventional images. A significant CNR improvement caused by MT remains at longer TR when there is no contrast enhancement without MT. The clinical results indicate that a single dose of Gd-DTPA combined with MT cannot replace imaging with a triple dose. However, MT significantly improved the CNR after single and triple Gd-DTPA-doses on T1-weighted and proton-density images.