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1.
PLoS One ; 16(10): e0258675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34662354

RESUMO

BACKGROUND: We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers. AIMS: To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants. METHODS: ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted. RESULTS: We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5). CONCLUSIONS: ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.

2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360890

RESUMO

The thylakoid lumen houses proteins that are vital for photosynthetic electron transport, including water-splitting at photosystem (PS) II and shuttling of electrons from cytochrome b6f to PSI. Other lumen proteins maintain photosynthetic activity through biogenesis and turnover of PSII complexes. Although all lumen proteins are soluble, these known details have highlighted interactions of some lumen proteins with thylakoid membranes or thylakoid-intrinsic proteins. Meanwhile, the functional details of most lumen proteins, as well as their distribution between the soluble and membrane-associated lumen fractions, remain unknown. The current study isolated the soluble free lumen (FL) and membrane-associated lumen (MAL) fractions from Arabidopsis thaliana, and used gel- and mass spectrometry-based proteomics methods to analyze the contents of each proteome. These results identified 60 lumenal proteins, and clearly distinguished the difference between the FL and MAL proteomes. The most abundant proteins in the FL fraction were involved in PSII assembly and repair, while the MAL proteome was enriched in proteins that support the oxygen-evolving complex (OEC). Novel proteins, including a new PsbP domain-containing isoform, as well as several novel post-translational modifications and N-termini, are reported, and bi-dimensional separation of the lumen proteome identified several protein oligomers in the thylakoid lumen.


Assuntos
Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Membranas Intracelulares/metabolismo , Complexo de Proteína do Fotossistema II/química , Complexo de Proteína do Fotossistema II/metabolismo , Proteoma , Tilacoides/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Eletroforese em Gel Bidimensional/métodos , Eletroforese em Gel de Poliacrilamida/métodos , Espectrometria de Massas/métodos , Fotossíntese/fisiologia , Complexo de Proteína do Fotossistema II/genética , Filogenia , Processamento de Proteína Pós-Traducional , Proteômica/métodos
3.
Artigo em Inglês | MEDLINE | ID: mdl-34281069

RESUMO

The demand for masculinizing breast surgery and hysterectomy with bilateral salpingo-oophorectomy (HBSO) from transmen has increased. With a multidisciplinary approach, these surgeries can be performed in a single session. The objective of this study was to retrospectively evaluate the feasibility, safety, and satisfaction of HBSO and chest surgery in transmen. A cohort of 142 subjects who underwent HBSO alone or combined with chest surgery at Sant'Orsola Hospital was analyzed. Intra and post operation events were evaluated. Subjective post-intervention satisfaction, acceptability, and impact of intervention were assessed via a semi-structured interview. Nineteen transmen underwent HBSO alone and 123 underwent combined surgery. HBSO was performed laparoscopically in 96.5% of transmen (137/142). As expected, length of hospital stay and blood loss were significantly higher in the combined surgery group. A total of 13 intra or post-operative complications occurred in the combined surgery group (10.5%) with thoracic hematoma being the most frequent complication (7.6%). Only one rare complication occurred in the HBSO group (omental herniation through a laparoscopic breach). The overall subjective satisfaction score was 9.9 out of 10 for both groups. Positive changes in all areas of life were reported, with no significant differences. We found that the combined surgery appears to be well tolerated, safe, and feasible in transmen and satisfaction with the combined procedure was high in all subjects.


Assuntos
Salpingo-Ooforectomia , Pessoas Transgênero , Estudos de Viabilidade , Feminino , Humanos , Histerectomia , Satisfação Pessoal , Estudos Retrospectivos
4.
Clin Chem Lab Med ; 59(10): 1699-1708, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34192831

RESUMO

OBJECTIVES: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. METHODS: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. RESULTS: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved. CONCLUSIONS: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.

5.
J Sex Med ; 18(5): 900-907, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33903046

RESUMO

BACKGROUND: Transgender people are a vulnerable group with a higher incidence of mental health issues and, during the COVID-19 outbreak, they may have faced psychological, physical and social obstacles. AIM: To evaluate the impact of the pandemic and the access to health care services during the COVID-19 pandemic on the mental health of the transgender people living in Italy. METHODS: An anonymous web-based survey was conducted among transgender people living in Italy. OUTCOMES: The survey consisted of 41 questions (to address socio-demographic and COVID-19 related variables, general health problems and trans-related health issues) and three validated questionnaires (the Impact of Event Scale [IES], the Beck Depression Inventory [BDI-II] and the SF-12. RESULTS: In total 108 respondents were included in the analysis, of these 73.1% were transmen and 26.9% transwomen. The mean age was 34.3 ± 11.7 years with 88.9% undergoing gender affirming hormonal treatment (GAHT). Of these respondents 55.6% were not working during the COVID-19 pandemic, mainly because they lost their jobs due to the lockdown (30.5%) or because they were otherwise unemployed (25.0%). Only four subjects were quarantined at home because of a positive COVID-19 swab. The mean total IES score was 21.1 ± 14.9 with 24.1% of subjects scoring over the cut-off score of 26 thereby suggesting a moderate-to-severe impact of the pandemic event. Mean BDI score was 8.6 ± 8.4. SF-12 total mean score was 96.1 ± 11.9 with a Mental Component Summary (MCS) score of 42.8 ± 9.1. Access to endocrinological consultations for hormonal prescription via telemedicine services was associated with better IES total scores (P = .01). CLINICAL IMPLICATIONS: Our results highlight the impact of the pandemic on the mental health of this particular population and how telemedicine services may serve to mitigate negative psychological effects. STRENGTHS & LIMITATIONS: Internet-based surveys may select a group of people not necessary representative of the whole population. The self-reporting bias should also be considered. Those who responded to our survey were mainly from northern Italy were COVID-19 has had a greater impact. CONCLUSION: Vulnerable groups such as the transgender population should receive more consideration also during pandemic events and their access to health services especially for endocrine and mental health care should be improved. A nationwide plan for the extended use of telemedicine should be established with targeted intervention to reduce psychological distress. Gava G, Fisher AD, Alvisi S, et al. Mental Health and Endocrine Telemedicine Consultations in Transgender Subjects During the COVID-19 Outbreak in Italy: A Cross-Sectional Web-Based Survey. J Sex Med 2021;18:900-907.


Assuntos
COVID-19 , Telemedicina , Pessoas Transgênero , Adulto , Controle de Doenças Transmissíveis , Estudos Transversais , Surtos de Doenças , Humanos , Internet , Itália/epidemiologia , Saúde Mental , Pessoa de Meia-Idade , Pandemias , Encaminhamento e Consulta , SARS-CoV-2 , Inquéritos e Questionários , Adulto Jovem
6.
J Sex Med ; 18(3): 646-655, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33531255

RESUMO

BACKGROUND: While the effects of androgens on muscle are well described in hypogonadal men, literature is still scarce on muscular strength or size variations in transmen; in this population there are no data regarding the relative effect of testosterone (T) and its metabolite dihydrotestosterone on muscle. AIM: Our primary objective was to compare the effects on muscle strength of 54-week administration of testosterone undecanoate (TU) combined with the 5α-reductase inhibitor dutasteride (DT) or placebo (PL). Secondary outcomes included evaluation of body composition, bone, cutaneous androgenic effects, and metabolic variations. METHODS: In this randomized, double-blind PL-controlled pilot trial, 16 ovariectomized transmen were randomized to receive TU 1,000 mg IM at week 0, 6, 18, 30, 42 plus a PL pill orally daily (TU + PL, n = 7) or plus DT 5 mg/d (TU + DT, n = 7). OUTCOMES: At week 0 and 54 the following parameters were evaluated: isokinetic knee extension and flexion peak torque and handgrip strength, body composition, and bone mineral density, biochemical, hematological, and hormonal parameters. RESULTS: Handgrip and lower limb strength increased significantly in both groups with no differences between the 2 groups. Fat mass decreased and lean mass increased significantly similarly in both groups. Metabolic parameters remained stable in the 2 groups except for high-density lipoprotein cholesterol that was reduced in both groups. Hepatic and renal function remained normal in both groups and no major adverse effects were registered in either group. CLINICAL IMPLICATIONS: These results may be particularly relevant for transmen experiencing cutaneous androgenic adverse events such as acne and androgenetic alopecia and in light of the development of non-5α-reduced androgens. STRENGTHS & LIMITATIONS: The strength of this study was the randomized, double-blind PL-controlled design, while the small number of subjects was definitely the biggest limitation. CONCLUSION: For the first time we demonstrated that the addition of DT does not impair the anabolic effects of T on muscles in transmen previously exposed to T, supporting the hypothesis that the conversion in dihydrotestosterone is not essential for this role. Gava G, Armillotta F, Pillastrini P, et al. A Randomized Double-Blind Placebo-Controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition, and Metabolic Profile in Transmen. J Sex Med 2021;18:646-655.


Assuntos
Força da Mão , Metaboloma , Composição Corporal , Método Duplo-Cego , Dutasterida/uso terapêutico , Humanos , Masculino , Força Muscular , Projetos Piloto , Testosterona/análogos & derivados
7.
Int J Impot Res ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558672

RESUMO

Sexual and reproductive issues are essential elements of well-being in cisgenders as well as for the transgender population. Gender-affirming hormonal treatments (GAHTs) aim to induce phenotypical changes congruent with the desired gender and subsequent reduction of gender dysphoria. While genital surgical procedures including hysterectomy and/or adenectomy cause permanent loss of ability to conceive, GAHT may induce a varying degree of reversible loss of fertility. For these reasons, transgender men and women need to be counseled concerning contraceptive options and potential effects of treatment on reproductive function before initiating GAHT. The literature reports that sexual activity with genital involvement is performed by less than half of transgender persons who have been sexually active with a partner in the past. Testosterone (T) is the most commonly used compound in transmen and usually leads to amenorrhea within 1-12 months from first administration, however cessation of menses does not mean anovulation. Some studies report cases of unintended pregnancies among transgender men under masculinizing therapy, therefore T treatment cannot be considered a contraceptive option. Currently available contraceptive options have pros and cons in transmen and scarce literature exists on their use. The effects of GAHT on fertility in transwomen are even less well known. Prolonged estrogen exposure induces sperm suppression and morphological changes of the spermatozoa, however the degree of resulting pregnancy protection is unclear. Further research to inform the contraceptive counseling in this population is mandatory.

8.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33514065

RESUMO

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.


Assuntos
Síndrome de Resistência a Andrógenos/tratamento farmacológico , Cromossomos Humanos X/genética , Terapia de Reposição Hormonal , Receptores Androgênicos/genética , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/patologia , Androgênios/uso terapêutico , Cromossomos Humanos X/efeitos dos fármacos , Feminino , Gônadas/efeitos dos fármacos , Humanos , Cariótipo , Masculino , Mutação/genética
9.
J Thromb Haemost ; 19(2): 513-521, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33230904

RESUMO

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients. OBJECTIVES: To investigate the mechanism of microthrombosis in COVID-19 progression. PATIENTS/METHODS: We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin-cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross-sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high-flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19). RESULTS: Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID-19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high-to-low molecular-weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care. CONCLUSIONS: We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis.


Assuntos
Proteína ADAMTS13/sangue , Coagulação Sanguínea , COVID-19/sangue , Trombose/sangue , Fator de von Willebrand/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/terapia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Trombose/diagnóstico , Trombose/etiologia
10.
Thromb Res ; 197: 132-137, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33212380

RESUMO

BACKGROUND: Deep vein thrombosis (DVT) is a common multi-factorial disease with a partially understood aetiology. Although the roles of high factor (F)VIII and von Willebrand factor (VWF) levels are recognized, that of ADAMTS13 is still unclear. AIM: To assess the association between ADAMTS13 activity levels, VWF antigen (VWF:Ag) and FVIII coagulant activity (FVIII:C) levels and DVT. MATERIALS AND METHODS: 365 Italian DVT patients and 292 age- and sex-matched controls were considered. Plasma ADAMTS13 activity was measured using FRETS-VWF73 assay. VWF:Ag and FVIII:C were measured using immunoassay and one-stage clotting assay (ACL TOP analyzer), respectively. Quartile analyses were performed to evaluate the individual association between ADAMTS13 activity, VWF:Ag, FVIII:C and DVT. The combined effect of high VWF levels (> 4th quartile) and low ADAMTS13 levels (< 1st quartile) was evaluated using binary variables. All models were age- and sex-adjusted. Estimated risks were reported as Odds ratio (OR) with 95% confidence intervals (CI). RESULTS: ADAMTS13 activity was lower in DVT patients (94% vs. 98% of controls). Patients with an ADAMTS13 activity <1st quartile (86%) showed a 1.6-fold increased risk of DVT (95%CI, 1.05-2.55). The combination of low ADAMTS13 activity and high VWF:Ag levels was associated with a 15-fold increased risk (95%CI, 7.80-33.80). VWF:Ag and FVIII:C were associated to DVT with a dose-response relationship. CONCLUSIONS: ADAMTS13 activity < 86% was associated with a moderate risk of DVT. The co-presence of low ADAMTS13 activity and high VWF levels resulted in a strong synergistic effect on DVT risk. The association of VWF:Ag and FVIII:C with DVT was confirmed.


Assuntos
Trombose Venosa , Fator de von Willebrand , Proteína ADAMTS13 , Testes de Coagulação Sanguínea , Causalidade , Fator VIII , Humanos , Itália , Trombose Venosa/etiologia
11.
Maturitas ; 143: 89-95, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33308642

RESUMO

OBJECTIVE: The objective of this study was to present an updated picture of the knowledge and attitudes of Italian gynecologists with regard to the genitourinary syndrome of menopause (GSM). STUDY DESIGN: An anonymous survey was sent via electronic mail to 3892 gynecologists. The survey consisted of 32 multiple-choice questions divided into four different areas: 1. general demographics of the respondents; 2. knowledge of GSM; 3. most frequently prescribed therapies; and 4. perception of patient compliance and satisfaction with current therapeutic options. MAIN OUTCOME MEASURES: Knowledge of vulvo-vaginal atrophy (VVA) and attitudes of the gynecologists to its management. RESULTS: Three hundred and seventy-four out of 3892 invited Italian gynecologists replied to the survey (response rate 9.7 %). Most (84 %) had a good knowledge of GSM and 74 % reported that they investigated it during clinic visits, but most of them underestimated its prevalence. The most frequently prescribed treatment was topical hormonal therapy (60 %), followed by vaginal moisturizers and lubricants (16 %), ospemifene (12 %) and systemic hormone therapy (12 %). According to the clinical experience of respondents, the most effective therapy is local hormonal therapy (36 %), followed by ospemifene (30 %). According to respondents, less than 50 % of patients continue therapy after 12 months, due to the discomfort in vaginal application, the cost of oral therapies and the fear of possible side-effects. CONCLUSIONS: With the limitation of the low response rate, this study suggests that although Italian gynecologists who answered the survey had some knowledge of GSM, they underestimated its prevalence, did not know its most bothersome symptoms and had inadequate knowledge of the efficacy of treatments, patient compliance and satisfaction.


Assuntos
Competência Clínica , Doenças Urogenitais Femininas , Ginecologia , Menopausa , Médicos , Atrofia , Atitude do Pessoal de Saúde , Feminino , Humanos , Itália , Masculino , Inquéritos e Questionários , Síndrome , Vagina/patologia , Vulva/patologia
12.
J Clin Med ; 9(10)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096882

RESUMO

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (ß -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

14.
Eur J Endocrinol ; 183(6): 561-569, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33055297

RESUMO

Objective: The impact of different combinations of long-term gender-affirming hormone therapy (GAHT) in transwomen (TW) is largely unknown. To assess the effects of 5-year administration of cyproterone acetate (CPA) or leuprolide acetate (Leu) plus transdermal or oral estradiol (E). Design: Cohort study based on prospectively collected data. Fifty TW received 50 mg CPA daily orally (n = 25; CPA+E group) or 3.75 mg Leu i.m. monthly (n = 25; Leu+E group) with 1 or 2 mg E daily for 5 years. Reproductive hormones, biochemical and anthropometric parameters, body composition and bone mineral density (BMD) were assessed. Results: LH, FSH and total testosterone levels were similarly and significantly suppressed in both groups. Prolactin increased only in the CPA+E group (P = 0.002). Fasting insulin resistance and glucose progressively increased in the CPA+E group only (treatment × time effect P = 0.002 and P = 0.043, respectively). Total cholesterol increased more in the Leu+E group than in the CPA+E group and HDL-cholesterol decreased in the CPA+E group (time × treatment interaction effect, P = 0.007). Lumbar and total body BMD increased in both groups after 3 years. No serious adverse events were recorded. Conclusions: Both regimens were effective in suppression of T production. CPA+E worsened the metabolic profile with a slight increase in PRL levels. All subjects presented an increase in BMD regardless of treatment. These preliminary data could have clinical implications in the choice of GAHT, in particular for those TW not requiring gender-affirming surgery.


Assuntos
Acetato de Ciproterona/administração & dosagem , Estradiol/administração & dosagem , Leuprolida/administração & dosagem , Testosterona/sangue , Transexualidade/sangue , Transexualidade/tratamento farmacológico , Adulto , Antagonistas de Androgênios/administração & dosagem , Estudos de Coortes , Esquema de Medicação , Quimioterapia Combinada , Estrogênios/administração & dosagem , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testosterona/antagonistas & inibidores , Pessoas Transgênero
15.
Proc Natl Acad Sci U S A ; 117(30): 17499-17509, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32690715

RESUMO

Coping of evergreen conifers in boreal forests with freezing temperatures on bright winter days puts the photosynthetic machinery in great risk of oxidative damage. To survive harsh winter conditions, conifers have evolved a unique but poorly characterized photoprotection mechanism, a sustained form of nonphotochemical quenching (sustained NPQ). Here we focused on functional properties and underlying molecular mechanisms related to the development of sustained NPQ in Norway spruce (Picea abies). Data were collected during 4 consecutive years (2016 to 2019) from trees growing in sun and shade habitats. When day temperatures dropped below -4 °C, the specific N-terminally triply phosphorylated LHCB1 isoform (3p-LHCII) and phosphorylated PSBS (p-PSBS) could be detected in the thylakoid membrane. Development of sustained NPQ coincided with the highest level of 3p-LHCII and p-PSBS, occurring after prolonged coincidence of bright winter days and temperatures close to -10 °C. Artificial induction of both the sustained NPQ and recovery from naturally induced sustained NPQ provided information on differential dynamics and light-dependence of 3p-LHCII and p-PSBS accumulation as prerequisites for sustained NPQ. Data obtained collectively suggest three components related to sustained NPQ in spruce: 1) Freezing temperatures induce 3p-LHCII accumulation independently of light, which is suggested to initiate destacking of appressed thylakoid membranes due to increased electrostatic repulsion of adjacent membranes; 2) p-PSBS accumulation is both light- and temperature-dependent and closely linked to the initiation of sustained NPQ, which 3) in concert with PSII photoinhibition, is suggested to trigger sustained NPQ in spruce.


Assuntos
Fotossíntese , Picea/fisiologia , Estações do Ano , Proteínas das Membranas dos Tilacoides/metabolismo , Tilacoides/metabolismo , Sequência de Aminoácidos , Meio Ambiente , Complexos de Proteínas Captadores de Luz/metabolismo , Noruega , Fosforilação , Espectrometria de Massas em Tandem , Proteínas das Membranas dos Tilacoides/química , Árvores
17.
Int J Lab Hematol ; 42(6): 685-696, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32672897

RESUMO

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH), by the ADAMTS13 Assay Working Group, which comprises an international group of both clinical and laboratory experts. The document provides recommendations on best practice for the performance of ADAMTS13 assays in clinical laboratories. ADAMTS13 assays support the differential diagnosis of thrombotic microangiopathies and have utility in the management of thrombotic thrombocytopenic purpura (TTP). There are three types of assay: activity, antigen and autoantibody/inhibitor assays. Methods for activity assays differ in terms of sensitivity, specificity, precision and turnaround time. The most widely used assays involve VWF peptide substrates and either chromogenic ELISA or FRET techniques, although chemiluminescence assays and rapid screening tests have recently become available. Tests for autoantibodies and inhibitors allow confirmation of acquired, immune-mediated TTP, while antigen assays may be useful in congenital TTP and as prognostic markers. In this document, we have attempted to describe ADAMTS13 assays and the conditions that affect them, as well as: blood collection, sample processing, quality control, standardization and clinical utility; recognizing that laboratories in different parts of the world have varying levels of sophistication. The recommendations are based on expert opinion, published literature and good clinical laboratory practice.


Assuntos
Proteína ADAMTS13/sangue , Hematologia/normas , Laboratórios Hospitalares/normas , Púrpura Trombocitopênica Trombótica , Controle de Qualidade , Microangiopatias Trombóticas , Humanos , Guias de Prática Clínica como Assunto , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/diagnóstico , Padrões de Referência , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/diagnóstico
18.
Blood ; 136(3): 353-361, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32356859

RESUMO

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.


Assuntos
Proteína ADAMTS13/sangue , Autoanticorpos/sangue , Púrpura Trombocitopênica Idiopática/sangue , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Conformação Proteica , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/administração & dosagem
19.
Eur J Intern Med ; 75: 79-83, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32201091

RESUMO

BACKGROUND: The prevalence of older patients with acquired thrombotic thrombocytopenic purpura (TTP) is increasing. There is scarce information on the prevalence of multimorbidity, polypharmacy and age-related diseases in aging TTP patients. This study aimed to evaluate the prevalence of multimorbidity and polypharmacy in a population of acquired TTP patients aged 65 years or more compared with a group of age-matched controls. METHODS: Acquired TTP patients enrolled in the Milan TTP registry from December 1st 1999 to March 31th 2018 and aged 65 years or more at the date of last follow-up were evaluated. Controls were Italian healthy individuals recruited from 2006 to March 31th 2018 among friends and non-consanguineous relatives of patients tested for thrombophilia screening at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan. RESULTS: 36 TTP patients and 127 age-matched controls were included. Compared with controls, TTP patients had a higher prevalence of multimorbidity and polypharmacy. They also showed a higher prevalence of autoimmune diseases, osteoporosis and arterial hypertension and were more chronically treated with corticosteroids and antiplatelets for primary cardiovascular prevention. All these results were confirmed after adjusting for sex. Compared with the general elderly population, TTP patients showed a higher prevalence of ischemic heart disease and stroke. CONCLUSIONS: Our findings suggest that a careful comprehensive geriatric assessment of acquired TTP patients is necessary. It is important to look for other autoimmune diseases and such age-related comorbidities as osteoporosis, arterial hypertension, ischemic heart disease and cerebrovascular disease.


Assuntos
Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13 , Idoso , Envelhecimento , Humanos , Itália/epidemiologia , Prevalência , Púrpura Trombocitopênica Trombótica/epidemiologia
20.
Haematologica ; 105(7): 1957-1962, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31558667

RESUMO

Neurological symptoms related to microthrombosis are the hallmark of acute manifestations of acquired thrombotic thrombocytopenic purpura (TTP). Despite the achievement of hematological remission, patients may report persisting neurological impairment that affects their quality of life. To assess the long-term neuropsychological consequences of acute TTP, we recruited 35 acquired TTP patients (77% females, median age at onset 41 years, interquartile range: 35-48) regularly followed at our out-patient clinic of thrombotic microangiopathies in Milan (Italy) from December 2015 to October 2016. Patients underwent a psychological evaluation of memory and attentional functions, emotional wellbeing and health-related quality of life at least three months after their last acute TTP event (median 36 months, interquartile range: 17-54). During the psychological consultation, 17 patients (49%) referred persisting subjective neurological impairment in the frame of a remission phase, with at least one symptom as disorientation, loss of concentration, dizziness, lack of balance, headache and diplopia. Neuropsychological assessment revealed lower scores than the Italian general population pertaining to direct, indirect and deferred memory. A higher degree of impairment of memory domains was found in patients with neurological involvement at the time of presentation of the first acute TTP episode. Anxiety and depression were detected in seven (20%) and 15 (43%) patients, respectively. Health-related quality of life was lower than the Italian general population, with mental domains more impacted than physical domains (mean difference 58.43, 95% confidence interval: 71.49-45.37). Our study demonstrates compromised memory and attention functions, persisting anxiety/depression symptoms and a generally reduced quality of life in patients recovering from acute acquired TTP. New clinical strategies should be considered to improve these symptoms.


Assuntos
Púrpura Trombocitopênica Trombótica , Qualidade de Vida , Adulto , Ansiedade/epidemiologia , Ansiedade/etiologia , Depressão/epidemiologia , Depressão/etiologia , Feminino , Humanos , Itália , Masculino , Transtornos da Memória/epidemiologia , Transtornos da Memória/etiologia , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/epidemiologia
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