Abstract Aim of the Study To induce puberty by transplantation of frozen/thawed ovarian tissue collected prior to gonadotoxic treatment for a cancer. Patients and Methods A 9-year-old girl with Ewing ...sarcoma had one ovary excised and cryopreserved prior to chemo- and radiotherapy. Functional activity of the remaining ovary was destroyed during treatment. Four and a half years later the girl remained pre-pubertal with postmenopausal levels of FSH. Two of ten pieces of frozen/thawed cortex were transplanted to the remaining ovary in order to stimulate puberty. Results Four months after the transplantation FSH returned to low levels. During the following year puberty gradually progressed to Tanner stage B4 and P3 and regular menstrual cycles started. However, after 19 months the function of the graft ceased. Conclusions We have shown for the first time in a girl treated for cancer that transplanted ovarian tissue can regain function and secrete estradiol in a sufficient amount to induce puberty. In addition, the majority of her ovarian tissue remains frozen with a possibility to support fertility in adult life.
Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, ...delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.
Engineering of materials with specific physical properties has recently focused on the effect of nano-sized 'guest domains' in a 'host matrix' that enable tuning of electrical, mechanical, ...photo-optical or thermal properties. A low thermal conductivity is a prerequisite for obtaining effective thermoelectric materials, and the challenge is to limit the conduction of heat by phonons, without simultaneously reducing the charge transport. This is named the 'phonon glass-electron crystal' concept and may be realized in host-guest systems. The guest entities are believed to have independent oscillations, so-called rattler modes, which scatter the acoustic phonons and reduce the thermal conductivity. We have investigated the phonon dispersion relation in the phonon glass-electron crystal material Ba(8)Ga(16)Ge(30) using neutron triple-axis spectroscopy. The results disclose unambiguously the theoretically predicted avoided crossing of the rattler modes and the acoustic-phonon branches. The observed phonon lifetimes are longer than expected, and a new explanation for the low kappa(L) is provided.
Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and ...extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways.
Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing.
Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04).
In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.
Mineral inclusions are common and have been widely used to investigate complex geological history. When a rock undergoes cooling and decompression after the entrapment of an inclusion into a host ...mineral, residual pressure may develop within the inclusion because of the differences in thermal expansivity and compressibility between the inclusion and host. By combining laser Raman spectroscopy and experimental data relating hydrostatic pressure and Raman shift, it is possible to estimate the entrapment pressure–temperature (
P
–
T
) conditions using an isotropic elastic model. In this study, we report Raman spectroscopic data on both zircon and quartz inclusions in garnet host from the Holsnøy eclogite, Bergen Arcs, Norway. Averaged residual pressures based on different Raman peaks for zircon and quartz inclusions are obtained to be ca. 0.6 GPa and ca. 0.65 GPa respectively. Using the equation of state for zircon and quartz, the entrapment
P
–
T
conditions are constrained to be 1.7–1.9 GPa, 680–760 °C, consistent with previous estimates based on phase equilibria. Heating/cooling experiments are performed on an entrapped zircon inclusion. A clear trend is found between the residual zircon inclusion pressure and the externally controlled temperature. We show that the residual zircon inclusion pressure sealed in garnet host is very sensitive to the entrapment temperature, and can be used as a Raman thermometer. The effects of laser heating and the thermo-elastic anisotropy of zircon inclusion are quantified and discussed.
The spread of farming from western Asia to Europe had profound long-term social and ecological impacts, but identification of the specific nature of Neolithic land management practices and the ...dietary contribution of early crops has been problematic. Here, we present previously undescribed stable isotope determinations of charred cereals and pulses from 13 Neolithic sites across Europe (dating ca . 5900–2400 cal B.C.), which show that early farmers used livestock manure and water management to enhance crop yields. Intensive manuring inextricably linked plant cultivation and animal herding and contributed to the remarkable resilience of these combined practices across diverse climatic zones. Critically, our findings suggest that commonly applied paleodietary interpretations of human and herbivore δ ¹⁵N values have systematically underestimated the contribution of crop-derived protein to early farmer diets.
Human neutrophil elastase (HNE) is an important N-glycosylated serine protease in the innate immune system, but the structure and immune-modulating functions of HNE N-glycosylation remain ...undescribed. Herein, LC-MS/MS-based glycan, glycopeptide and glycoprotein profiling were utilized to first determine the heterogeneous N-glycosylation of HNE purified from neutrophil lysates and then from isolated neutrophil granules of healthy individuals. The spatiotemporal expression of HNE during neutrophil activation and the biological importance of its N-glycosylation were also investigated using immunoblotting, cell surface capture, native MS, receptor interaction, protease inhibition, and bacteria growth assays. Site-specific HNE glycoprofiling demonstrated that unusual paucimannosidic N-glycans, particularly Manα1,6Manβ1,4GlcNAcβ1,4(Fucα1,6)GlcNAcβ, predominantly occupied Asn124 and Asn173. The equally unusual core fucosylated monoantenna complex-type N-sialoglycans also decorated these two fully occupied sites. In contrast, the mostly unoccupied Asn88 carried nonfucosylated paucimannosidic N-glycans probably resulting from low glycosylation site solvent accessibility. Asn185 was not glycosylated. Subcellular- and site-specific glycoprofiling showed highly uniform N-glycosylation of HNE residing in distinct neutrophil compartments. Stimulation-induced cell surface mobilization demonstrated a spatiotemporal regulation, but not cell surface-specific glycosylation signatures, of HNE in activated human neutrophils. The three glycosylation sites of HNE were located distal to the active site indicating glycan functions other than interference with HNE enzyme activity. Functionally, the paucimannosidic HNE glycoforms displayed preferential binding to human mannose binding lectin compared with the HNE sialoglycoforms, suggesting a glycoform-dependent involvement of HNE in complement activation. The heavily N-glycosylated HNE protease inhibitor, α1-antitrypsin, displayed concentration-dependent complex formation and preferred glycoform-glycoform interactions with HNE. Finally, both enzymatically active HNE and isolated HNE N-glycans demonstrated low micromolar concentration-dependent growth inhibition of clinically-relevant Pseudomonas aeruginosa, suggesting some bacteriostatic activity is conferred by the HNE N-glycans. Taken together, these observations support that the unusual HNE N-glycosylation, here reported for the first time, is involved in modulating multiple immune functions central to inflammation and infection.
Cardiovascular disease is emerging as a cardinal trait of Turner syndrome, being responsible for half of the 3-fold excess mortality. Turner syndrome has been proposed as an independent risk marker ...for cardiovascular disease that manifests as congenital heart disease, aortic dilation and dissection, valvular heart disease, hypertension, thromboembolism, myocardial infarction, and stroke. Risk stratification is unfortunately not straightforward because risk markers derived from the general population inadequately identify the subset of females with Turner syndrome who will suffer events. A high prevalence of endocrine disorders adds to the complexity, exacerbating cardiovascular prognosis. Mounting knowledge about the prevalence and interplay of cardiovascular and endocrine disease in Turner syndrome is paralleled by improved understanding of the genetics of the X-chromosome in both normal health and disease. At present in Turner syndrome, this is most advanced for the SHOX gene, which partly explains the growth deficit.
This review provides an up-to-date condensation of current state-of-the-art knowledge in Turner syndrome, the main focus being cardiovascular morbidity and mortality. The aim is to provide insight into pathogenesis of Turner syndrome with perspectives to advances in the understanding of genetics of the X-chromosome. The review also incorporates important endocrine features, in order to comprehensively explain the cardiovascular phenotype and to highlight how raised attention to endocrinology and genetics is important in the identification and modification of cardiovascular risk.
The Changing Face of Turner Syndrome Gravholt, Claus H; Viuff, Mette; Just, Jesper ...
Endocrine reviews,
01/2023, Volume:
44, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
Turner syndrome (TS) is a condition in females missing the second sex chromosome (45,X) or parts thereof. It is considered a rare genetic condition and is associated with a wide range of ...clinical stigmata, such as short stature, ovarian dysgenesis, delayed puberty and infertility, congenital malformations, endocrine disorders, including a range of autoimmune conditions and type 2 diabetes, and neurocognitive deficits. Morbidity and mortality are clearly increased compared with the general population and the average age at diagnosis is quite delayed. During recent years it has become clear that a multidisciplinary approach is necessary toward the patient with TS. A number of clinical advances has been implemented, and these are reviewed. Our understanding of the genomic architecture of TS is advancing rapidly, and these latest developments are reviewed and discussed. Several candidate genes, genomic pathways and mechanisms, including an altered transcriptome and epigenome, are also presented.
Graphical Abstract
Graphical Abstract
L‐3,4‐Dihydroxyphenylalanine (L‐DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L‐DOPA‐induced dyskinesia in more than half ...the patients after 10 years of treatment. L‐DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L‐DOPA‐induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L‐DOPA‐induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1–2 h after intake of L‐DOPA or other anti‐Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L‐DOPA (n = 8), patients treated with L‐DOPA without dyskinesia (n = 8), and patients with L‐DOPA‐induced dyskinesia (n = 10) using liquid chromatography‐mass spectrometry. We observed approximately fourfold increase in the 3‐hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L‐DOPA‐induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5‐Hydroxytryptophan levels were twofold increased in all L‐DOPA‐treated Parkinson's patients. We conclude that a higher 3‐hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L‐DOPA‐induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L‐DOPA‐induced dyskinesia.
We observed marked changes in kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients with L‐DOPA‐induced dyskinesia as compared to controls or non‐dyskinetic Parkinson's patients. We suggest that an increased ratio of 3‐hydroxykynurenine/kynurenic acid in plasma may serve as a biomarker and may play a role in the pathopysiology of L‐DOPA‐induced dyskinesia.
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