Primary ovarian insufficiency (POI) is characterized by a loss of ovarian function before the age of 40 and account for one major cause of female infertility. POI relevance is continuously growing ...because of the increasing number of women desiring conception beyond 30 years of age, when POI prevalence is >1%. POI is highly heterogeneous and can present with ovarian dysgenesis and primary amenorrhea, or with secondary amenorrhea, and it can be associated with other congenital or acquired abnormalities. In most cases POI remains classified as idiopathic. However, the age of menopause is an inheritable trait and POI has a strong genetic component. This is confirmed by the existence of several candidate genes, experimental and natural models. The variable expressivity of POI defect may indicate that, this disease may frequently be considered as a multifactorial or oligogenic defect. The most common genetic contributors to POI are the X chromosome‐linked defects. Here, we review the principal X‐linked and autosomal genes involved in syndromic and non‐syndromic forms of POI with the expectation that this list will soon be upgraded, thus allowing the possibility to predict the risk of an early age at menopause in families with POI.
Abstract
STUDY QUESTION
Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a ...deleterious effect on ovarian function?
SUMMARY ANSWER
This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms.
WHAT IS KNOWN ALREADY
POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated.
STUDY DESIGN, SIZE, DURATION
The current study included 67 46,XX patients with early onset POI (<19 years) and 134 control females recruited between 2012 and 2016 at the Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano.
PARTICIPANTS/MATERIALS, SETTING, METHODS
High resolution array-CGH analysis was carried out on POI patients’ DNA. Results of patients and female controls were analyzed to search for rare CNVs. All variants were validated and subjected to a gene content analysis and disease gene prioritization based on the present literature to find out new ovary candidate genes. Case-control study with statistical analysis was carried out to validate our approach and evaluate any ovary CNVs/gene enrichment. Characterization of particular CNVs with molecular and functional studies was performed to assess their pathogenic involvement in POI.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified 37 ovary-related CNVs involving 44 genes with a role in ovary in 32 patients. All except one of the selected CNVs were not observed in the control group. Possible involvement of the CNVs in POI pathogenesis was further corroborated by a case-control analysis that showed a significant enrichment of ovary-related CNVs/genes in patients (P = 0.0132; P = 0.0126). Disease gene prioritization identified both previously reported POI genes (e.g. BMP15, DIAPH2, CPEB1, BNC1) and new candidates supported by transcript and functional studies, such as TP63 with a role in oocyte genomic integrity and VLDLR which is involved in steroidogenesis.
LARGE SCALE DATA
ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/); accession numbers SCV000787656 to SCV000787743.
LIMITATIONS, REASONS FOR CAUTION
This is a descriptive analysis for almost all of the CNVs identified. Inheritance studies of CNVs in some non-familial sporadic cases was not performed as the parents’ DNA samples were not available. Addionally, RT-qPCR analyses were carried out in few cases as RNA samples were not always available and the genes were not expressed in blood.
WIDER IMPLICATIONS OF THE FINDINGS
Our array-CGH screening turned out to be efficient in identifying different CNVs possibly implicated in disease onset, thus supporting the extremely wide genetic heterogeneity of POI. Since almost 50% of cases are negative rare ovary-related CNVs, array-CGH together with next generation sequencing might represent the most suitable approach to obtain a comprehensive genetic characterization of POI patients.
STUDY FUNDING/COMPETING INTEREST(S)
Supported by Italian Ministry of Health grants ‘Ricerca Corrente’ (08C203_2012) and ‘Ricerca Finalizzata’ (GR-2011-02351636, BIOEFFECT) to IRCCS Istituto Auxologico Italiano.
Ureteropelvic junction obstruction (UPJO) is a congenital or acquired functionally significant impairment of urinary transport from the renal pelvis to the ureter. Congenital UPJO typically results ...from intrinsic disease such as the presence of an aperistaltic segment of the ureter, aberrant vessels or kidney abnormalities. Rare conditions can sometimes mimic an UPJO. We present a case of an 86-year-old woman with a UPJO diagnosed on CT. The patient was counseled on treatment options and elected to undergo a left uretherorenoscopy (URS) plus left laparoscopic pyeloplasty. The definitive histopathologic diagnosis was perinephric myxoid pseudotumor of fat, an extremely rare neoplasm, mass-forming. To the best of our knowledge, this is the first known case of a pseudotumor of fat causing UPJO. 6-month follow-up showed neither recurrence nor residual UPJO. We describe a rare presentation of extrinsic perinephric myxoid pseudotumor of fat causing UPJ obstruction. In elderly patients with no history of malignancy, UPJ obstruction can occur because of atypical masses.
Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARgamma (peroxisome-proliferator-activated receptor gamma) ligand ...activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase approximately 20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-gamma; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the (*)NO (nitric oxide) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARgamma and *NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-kappaB (nuclear factor kappaB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.
Aim
Aortic stenosis is a frequent valvular disease, with transcatheter aortic valve implantation (TAVI) being performed when surgical replacement is at increased risk. However, TAVI-induced effects ...on myocardial efficiency are unknown. We aimed to investigate changes in LV mechano-energetic pre-/post-TAVI and their prognostic impact.
Methods
A total of 46 patients (25 males) received transesophageal and simultaneous radial pressure plus transaortic gradient monitoring before/immediately after prosthesis deployment. Efficiency was computed as external work/potential energy, as derived from LV pressure–volume plots; myocardial oxygen consumption (MVO
2
) was estimated as PWI
mod
, i.e. a noninvasively validated alternative for MVO
2
estimation.
Results
TAVI was successful in all patients, peak transaortic gradient decreasing − 40 ± 20 mmHg (
p
< 0.001). Efficiency improved post-TAVI (+ 0.6 ± 0.12;
p
= 0.004), with a concomitant PWI
mod
reduction (− 16 ± 31%;
p
< 0.001). When contextualized to fixed PWI
mod
value (5 ml/min/100 g), efficiency significantly affected survival (
p
= 0.029). Over 1026 ± 450-day follow-up, a change in efficiency pre-/post-TAVI ≤ 0.021 (median of the difference) predicted more deaths from any cause (30%) as compared with a change > 0.021 (17%), particularly in those patients with a pre-TAVI mean high-gradient (HG ≥ 40 mmHg) phenotype (
p
< 0.05). In particular, HG patients exhibited the lowest efficiency/PWI
mod
ratio pre-/post-TAVI (
p
= 0.048), relative to the other aortic stenosis patients, suggestive of an unfavourable matching between cardiac function and metabolic demand, which foreshortens some intrinsic damaged muscle condition in these patients.
Conclusion
LV mechanical efficiency improves immediately post-TAVI, notwithstanding an inhomogeneous mechano-energetic matching among the aortic stenosis patients, which can impact negatively on their long-term prognosis, particularly in those with the HG phenotype.
Graphic abstract
Dopamine-agonist drugs are the treatment of choice for most patients with hyperprolactinemia
1
,
2
. Bromocriptine has been the reference compound and effectively suppresses prolactin secretion, ...restores gonadal function, and shrinks prolactinomas
3
. It has a number of side effects, however, including nausea, dizziness, and headache, that limit the dose and may even necessitate the withdrawal of treatment
4
–
6
. Furthermore, its half-life is short so that it must be given two or three times daily.
Cabergoline is a new, selective, potent, and long-lasting dopamine agonist that inhibits prolactin secretion in both normal subjects and those with hyperprolactinemia, with a duration . . .
Summary
Objective The long‐term efficacy and safety of stereotactic radiosurgery by gamma knife (GK) still remain unknown. The aim of the study was to investigate the long‐term efficacy and ...tolerability of GK in acromegalic patients.
Design and patients Retrospective analysis for a median follow‐up of 10 years. Thirty‐five acromegalic patients from two referral centres in Milan submitted to GK (median margin dose: 20 Gy, median % isodose: 50) between 1995 and 2004.
Main outcome measures GH/IGF‐I secretion, anterior pituitary function, radiological imaging and ophthalmological data.
Results Cure rate improved over time (up to 46% at 10 years), as did the proportion of patients achieving control on somatostatin analogues (from 12·5% at baseline to 50% at 10 years). Normal IGF‐I values were observed in 82% of patients at their last visit. No visual impairment, disease recurrence, tumour growth or secondary cerebral tumour occurred. Half of the patients developed one or more new deficiencies, while two patients normalized their prior failures. In particular, new onset of clinical or subclinical hypoadrenalism occurred in 12/30 patients (40%), hypothyroidism in 3/28 (11%), hypogonadism in 2/15 (13%) and GH deficiency in 2/35 (6%). GH value at the time of GK was the best negative predictor of cure and margin dose was the best positive predictor of new hypopituitarism.
Conclusions Over a 10‐year period after GK radiosurgery, an increasing percentage of patients achieve cure, or adequate control of the disease on pharmacological therapy, at the expense of increasing novel pituitary deficiencies.
We report for the first time the electrochemical synthesis in anodic and cathodic conditions of anion-conducting ionomer separators using two different precursors: N-(p-vinylbenzyl) ...N,N,N-trimethylammonium chloride (VBTMA) and (N-allyl N-benzyl N,N-dimethyl)ammonium iodide (ABDMA). The ionomer structure and microstructure are investigated by NMR and FTIR spectroscopies and Scanning Electron Microscopy. The quaternary ammonium groups are grafted in side chains (VBTMA) or are near the main chain (ABDMA). The anion conductivity is in the order of 1 mS/cm with quaternary ammonium groups in side chains and lower when the ammonium groups are near the main chain, where they probably reduce the anion mobility by steric hindrance. Such thin-film anion exchange membranes are a valuable asset for the realization of microfuel cells and solid-state water electrolysers.
•Anion exchange membranes prepared by electrochemical synthesis.•Cathodic and anodic deposition conditions are explored.•Grafting of quaternary ammonium groups on side chains improves conductivity.
The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients ...(T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters.
Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on ...body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes.
One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months.
Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide.
Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.
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