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- Arponen, H, et al.
(author)
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Positive airway pressure therapy for obstructive sleep apnea in patients with Osteogenesis imperfecta: a prospective pilot study
- 2021
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In: BMC musculoskeletal disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 22:1, s. 61-
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Journal article (peer-reviewed)abstract
- BackgroundObstructive sleep apnea (OSA) is prevalent in individuals with Osteogenesis imperfecta (OI). To date, no study has investigated treatment of OSA in adult individuals with OI using positive airway pressure (PAP). This observational pilot study examined the adherence of adults with OI to treatment of OSA with PAP therapy, and the evolution of self-experienced sleepiness and depression symptoms before and after treatment.MethodsWe included 20 patients, with a mean age of 51 years, who represented varying severity of OI and displayed an apnea and hypopnea index ≥ 5 /sleeping hour as recorded by an overnight polysomnography. PAP therapy was proposed to all patients. Epworth Sleepiness Scale (ESS) questionnaire to evaluate daytime sleepiness, and a validated self-rating depression questionnaire to identify possible depression, were completed prior to PAP therapy and repeated after a minimum of one year. The datasets supporting the conclusions of this article are included within the article.ResultsFrom the 20 patients, 15 initiated PAP therapy, and two patients later interrupted it. The mean PAP follow-up period was 1230 days. At baseline, an abnormally high ESS score was reported by 29% of the respondents, and an abnormally high number of symptoms suggesting depression by 29%. Follow-up questionnaires were completed by 60% of the patients, of whom 83% were adherent to PAP treatment. ESS score and depression symptoms did not decrease significantly with PAP therapy.ConclusionsPatients with OI accepted well PAP therapy and remained compliant. Sleepiness and depression persisted unaltered despite good PAP adherence. These unexpectedly poor improvements in symptoms by PAP therapy may be due to subjective depression symptoms and the complexity of factors underlying persisting sleepiness in OI. Further research is needed to confirm this novel finding.
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- Viljakainen, H., et al.
(author)
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Low Copy Number of the AMY1 Locus Is Associated with Early-Onset Female Obesity in Finland
- 2015
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- Background The salivary alpha-amylase locus (AMY1) is located in a highly polymorphic multi allelic copy number variable chromosomal region. A recent report identified an association between AMY1 copy numbers and BMI in common obesity. The present study investigated the relationship between AMY1 copy number, BMI and serum amylase in childhood-onset obesity. Sixty-one subjects with a history of childhood-onset obesity (mean age 19.1 years, 54% males) and 71 matched controls (19.8 yrs, 45% males) were included. All anthropometric measures were greater in the obese; their mean BMI was 40 kg/m(2) (range 25-62 kg/m(2)) compared with 23 kg/m(2) in the controls (15-32 kg/m(2)). Mean AMY1 copy numbers did not differ between the obese and control subjects, but gender differences were observed; obese men showed the highest and obese women the lowest number of AMY1 copies (p=0.045). Further, only in affected females, AMY1 copy number correlated significantly with whole body fat percent (r=-0.512, p=0.013) and BMI (r=-0.416, p=0.025). Finally, a clear linear association between AMY1 copy number and serum salivary amylase was observed in all subgroups but again differences existed between obese males and females. In conclusion, our findings suggest that AMY1 copy number differences play a role in childhood-onset obesity but the effect differs between males and females. Further studies in larger cohorts are needed to confirm these observations.
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- Costantini, A, et al.
(author)
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Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia
- 2021
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In: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 12, s. 680838-
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Journal article (peer-reviewed)abstract
- Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic TRIP11 variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in TRIP11 and four likely pathogenic missense variants in FKBP10, TBX5, NEK1, and NBAS in the index patient. Interestingly, all these genes except TBX5 are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the TRIP11 mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.
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- Makitie, R. E., et al.
(author)
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Skeletal Characteristics of WNT1 Osteoporosis in Children and Young Adults
- 2016
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In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 31:9, s. 1734-1742
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Journal article (peer-reviewed)abstract
- WNT proteins comprise a 19-member glycoprotein family that act in several developmental and regenerative processes. In bone, WNT proteins regulate osteoblast differentiation and maintain bone health by activating the canonical WNT/-catenin pathway. We reported a heterozygous missense mutation c.652T>G (p.C218G) in WNT1 exon 4 as the cause for severe early-onset, autosomal dominant osteoporosis. The initial study concerned a large Finnish family with 10 affected adults. Here we report clinical findings of the WNT1 osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1. Clinical assessments showed no apparent dysmorphia or features similar to typical osteogenesis imperfecta (OI). Biochemistry revealed no changes in parameters of calcium metabolism and bone turnover markers. Fracture frequencies varied, but all subjects had sustained at least one fracture and 4 had a pathological fracture history. Plain radiographs showed osteopenic appearance, loss in vertebral height, and thin diaphyses of the long bones. Bone densitometry showed the BMD to be below normal median in all subjects and the bone mass deficit seemed to be more severe in older participants. Bone histomorphometry revealed a low turnover osteoporosis in 2 subjects at ages 14 and 16 years. These findings are congruent with earlier findings in adult patients and indicate that WNT1 osteoporosis causes significant skeletal changes already in early childhood and impairs bone mass gain during pubertal years. Genetic testing of children or close relatives of affected individuals is recommended for appropriate preventive measures. (c) 2016 American Society for Bone and Mineral Research.
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- Tuomela, Johanna, et al.
(author)
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Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors
- 2009
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9
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Journal article (peer-reviewed)abstract
- Background: Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. Methods: We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. Results: VEGFR3- Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001). Conclusion: The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.
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- Valta, Maija P, et al.
(author)
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FGF-8 is involved in bone metastasis of prostate cancer
- 2008
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 123:1, s. 22-31
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Journal article (peer-reviewed)abstract
- Prostate cancer is the most common malignancy of men in Western countries. Patients with advanced prostate cancer suffer from incurable bone metastases. Recent data indicate that interactions between prostate cancer cells, osteoblasts, osteoclasts and the bone matrix are essential in the formation of bone metastases. FGF-8 is widely overexpressed in prostate cancer. Recently, FGF-8 has been found to affect both osteoblast and osteoclast differentiation. The aim of this study was to examine the role of FGF-8 in bone metastasis of prostate cancer. Immunohistochemistry was used to analyse FGF-8 expression in clinical samples of prostate cancer bone metastases. The functional significance of FGF-8 in growth of bone metastasis and formation of bone lesions was verified by using intratibial inoculations of FGF-8 or mock transfected PC-3 prostate cancer cells in nude mice. Intratibial tumors and bone lesions were analysed with X-ray, micro-CT and detailed histomorphometry using image analysis software and with immunostaining for osteocalcin and cathepsin K. Immunohistochemical analysis of tissue microarray of bone metastases of human prostate cancer showed that 76% of human bone metastasis samples (n = 25 from 11 patients) were positive for FGF-8. FGF-8 increased the growth of intratibial tumors and local formation of lvtic and sclerotic lesions of bone. These results demonstrate that PGF-8 is expressed at a high frequency in bone metastases of human prostate cancer and that expression of FGF-8 in PC-3 prostate cancer cells increases their growth as intratibial tumors and modulates formation of bone lesions in an in vivo model of prostate cancer bone metastasis.
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