Testicular function in males with infantile nephropathic cystinosis.

STUDY QUESTION: Do males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood? SUMMARY ANSWER: Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood. WHAT IS KNOWN ALREADY: Biallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: Adherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery. LIMITATIONS, REASONS FOR CAUTION: Limitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.

The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: Scrotal ultrasound reference ranges and associations with clinical, seminal, and biochemical characteristics.

BACKGROUND: Scrotal color Doppler ultrasound (CDUS) still suffers from lack of standardization. Hence, the European Academy of Andrology (EAA) has promoted a multicenter study to assess the CDUS characteristics of healthy fertile men (HFM) to obtain normative parameters. OBJECTIVES: To report and discuss the scrotal organs CDUS reference ranges and characteristics in HFM and their associations with clinical, seminal, and biochemical parameters. METHODS: A cohort of 248 HFM (35.3 ± 5.9years) was studied, evaluating, on the same day, clinical, biochemical, seminal, and scrotal CDUS following Standard Operating Procedures. RESULTS: The CDUS reference range and characteristics of the scrotal organs of HFM are reported here. CDUS showed a higher accuracy than physical examination in detecting scrotal abnormalities. Prader orchidometer (PO)- and US-measured testicular volume (TV) were closely related. The US-assessed TV with the ellipsoid formula showed the best correlation with the PO-TV. The mean TV of HFM was ~ 17 ml. The lowest reference limit for right and left testis was 12 and 11 ml, thresholds defining testicular hypotrophy. The highest reference limit for epididymal head, tail, and vas deferens was 12, 6, and 4.5 mm, respectively. Mean TV was associated positively with sperm concentration and total count and negatively with gonadotropins levels and pulse pressure. Subjects with testicular inhomogeneity or calcifications showed lower sperm vitality and concentration, respectively, than the rest of the sample. Sperm normal morphology and progressive motility were positively associated with epididymal head size/vascularization and vas deferens size, respectively. Increased epididymis and vas deferens sizes were associated with MAR test positivity. Decreased epididymal tail homogeneity/vascularization were positively associated with waistline, which was negatively associated with intratesticular vascularization. CDUS varicocele was detected in 37.2% of men and was not associated with seminal or hormonal parameters. Scrotal CDUS parameters were not associated with time to pregnancy, number of children, history of miscarriage. CONCLUSIONS: The present findings will help in better understanding male infertility pathophysiology, improving its management.

Citizen approval of nudging interventions promoting healthy eating: the role of intrusiveness and trustworthiness.

BACKGROUND: Nudging interventions have lately been widely adopted by policy makers to increase the welfare of society and to help citizens make better choices. Hence, it has become important to understand the conditions under which they are approved. While most research has looked into whether professionals approve of nudging interventions, surprisingly the opinion of the target group has been widely ignored. This study investigated citizens' level of approval of nudging in the realm of healthy eating promotion, as well as its boundary conditions. METHODS: Participants (N = 1441) from the US and seven European countries were probed for their level of approval of nudges. Moreover, we investigated whether these levels of approval were dependent on the level of intrusiveness of the nudge and on the type and trustworthiness of the source (policy makers, experts, industry) implementing the nudge. RESULTS: People revealed moderate to high levels of approval with nudging across all countries. Intrusiveness and nudging approval were negatively associated. Nudges implemented by experts received more approval than those by policy makers. In general, approval increased with the trustworthiness of the source. CONCLUSIONS: These results provide information for European and American policy makers considering using nudging in their policy repertoire.

A history of undescended testes in young men with Klinefelter syndrome does not reduce the chances for successful microsurgical testicular sperm extraction.

Klinefelter syndrome (KS) and undescended testes (UDT) are known etiologies for non-obstructive azoospermia (NOA), and coexistence of both etiologies is not uncommon. Patients with both KS and a history of UDT are therefore considered to have extremely reduced chances for paternity. We aimed to analyze the impact of previous surgically corrected unilateral or bilateral UDT on sperm retrieval rates (SRRs) by microsurgical testicular sperm extraction (mTESE) in azoospermic men with KS. Age, testicular volumes, and hypothalamo-pituitary-gonadal axis function were investigated in relation to SRRs in 29 non-mosaic KS patients (47,XXY) with a history of UDT (group 1) who underwent mTESE between 2008 and 2016 in our center and compared to the data of age- and serum testosterone-matched non-mosaic KS controls with eutopic testes at birth (group 2), and to those of 51 men with NOA and a normal male karyotype (46,XY), but previous UDT (group 3). SRRs in KS patients with surgically corrected UDT during childhood were comparable to SRRs of KS patients with eutopic testes at birth: 31% (35% in unilateral and 22% in bilateral UDT) vs. 38% (p = 0.581). SRRs and Leydig cell function in group 1 were negatively correlated with age. Significantly higher SRRs (66%) were found in euploid azoospermic men with surgically corrected UDT (p < 0.001). A history of UDT does not preclude chances for future fatherhood in young azoospermic males with KS. In one of three men with previous unilateral UDT and in one of 4-5 in those with previous bilateral UDT, spermatozoa can be harvested by mTESE during late adolescence or young adulthood for immediate or future use in assisted reproduction.

A theranostic dental pulp capping agent with improved MRI and CT contrast and biological properties.

Different materials have been used for vital dental pulp treatment. Preferably a pulp capping agent should show appropriate biological performance, excellent handling properties, and a good imaging contrast. These features can be delivered into a single material through the combination of therapeutic and diagnostic agents (i.e. theranostic). Calcium phosphate based composites (CPCs) are potentially ideal candidate for pulp treatment, although poor imaging contrast and poor dentino-inductive properties are limiting their clinical use. In this study, a theranostic dental pulp capping agent was developed. First, imaging properties of the CPC were improved by using a core-shell structured dual contrast agent (csDCA) consisting of superparamagnetic iron oxide (SPIO) and colloidal gold, as MRI and CT contrast agent respectively. Second, biological properties were implemented by using a dentinogenic factor (i.e. bone morphogenetic protein 2, BMP-2). The obtained CPC/csDCA/BMP-2 composite was tested in vivo, as direct pulp capping agent, in a male Habsi goat incisor model. Our outcomes showed no relevant alteration of the handling and mechanical properties (e.g. setting time, injectability, and compressive strength) by the incorporation of csDCA particles. In vivo results proved MRI contrast enhancement up to 7weeks. Incisors treated with BMP-2 showed improved tertiary dentin deposition as well as faster cement degradation as measured by µCT assessment. In conclusion, the presented theranostic agent matches the imaging and regenerative requirements for pulp capping applications. STATEMENT OF SIGNIFICANCE: In this study, we combined diagnostic and therapeutic agents in order to developed a theranostic pulp capping agent with enhanced MRI and CT contrast and improved dentin regeneration ability. In our study we cover all the steps from material preparation, mechanical and in vitro characterization, to in vivo study in a goat dental model. To the best of our knowledge, this is the first time that a theranostic pulp capping material have been developed and tested in an in vivo animal model. Our promising results in term of imaging contrast enhancement and of induction of new dentin formation, open a new scenario in the development of innovative dental materials.

Can germ cell neoplasia in situ be diagnosed by measuring serum levels of microRNA371a-3p?

PURPOSE: Diagnosing germ cell neoplasia in situ (GCNis) can detect germ cell tumours (GCTs) at the pre-invasive stage. To date, testicular biopsy with the potential of surgical complications is the only way of safely diagnosing GCNis. Recently, microRNAs (miRs) 371-3, and miR 367 were shown to be valuable serum biomarkers of GCTs. We explored the usefulness of these candidate miRs as a marker for GCNis. METHODS: 27 patients with GCNis and no concomitant GCT were enrolled. All patients underwent measuring serum levels of miR-371a-3p and miR-367-3p before treatment, 11 had repeat measurement after treatment, 2 also had testicular vein blood examinations. Serum levels were measured by quantitative PCR. In addition, four orchiectomy specimens of patients with GCT were examined immunohistochemically and by in situ hybridization (ISH) with a probe specific for miR-371a-3p to look for the presence of this miR in GCNis cells. RESULTS: The median serum level of miR-371a-3p was significantly higher in patients with GCNis than in controls, miR-367 levels were not elevated. Overall, 14 patients (51.9%) had elevated serum levels of miR-371a-3p. The highest levels were found in patients with bilateral GCNis. Levels in testicular vein serum were elevated in both of the cases. After treatment, all elevated levels dropped to normal. In two orchiectomy specimens, miR-371a-3p was detected by ISH in GCNis cells. CONCLUSIONS: Measuring miR-371a-3p serum levels can replace control biopsies after treatment of GCNis. In addition, the test can guide clinical decision making regarding the need of testicular biopsy in cases suspicious of GCNis.

Medical liability insurance claims after treatment of varicose veins.

OBJECTIVE: Since insight into the reason for filing claims after treatment of varicose veins of the lower extremity might help prevent future claims, we determined the incidence of and reasons for medical liability insurance claims after such treatments in the Netherlands. METHOD: We performed a retrospective review of all medical liability insurance claims after varicose vein treatment handled by MediRisk between January 1993 and December 2007. RESULTS: A total of 144 claims were filed of which 104 were closed by the end of the study period. Nerve injury (n = 28), skin necrosis following sclerotherapy (n = 17), deep vein injury (n = 11) and insufficient communication (n = 9) accounted for more than 60% of all claims. Claims were equally distributed among registrars and consultants. Some 41 of the 104 closed claims were accepted. In 27 of the accepted cases, the physician had obviously failed in providing the care as expected from a medical practitioner allowed to perform these treatments. The majority of these 27 claims were due to injury of nerves (n = 11) or deep veins (n = 9). CONCLUSION: The incidence of claims after treatment of varicose veins in the Netherlands is low. Proper knowledge of anatomy and adequate communication, along with the introduction of less invasive treatments might prevent future claims.

[Impulse control behaviors associated with antiparkinsonian medications]. / Les troubles du contrôle des impulsions associés au traitement dopaminergique substitutif antiparkinsonien.

In some patients, impulse control behaviours can be triggered by dopaminergic replacement therapy, particularly dopamine agonist drugs: hobbyism, punding (stereotyped behaviours), compulsive buying, binge eating disorder, pathological gamgling, hypersexuality, hedonistic homeostatic dysregulation syndrome ... The pathogenesis of these behaviours: is not well understood, but likely involves aberrant changes in the dopaminergic pathways that mediate motivation i.e., a dopaminergic "overdose" in meso-cortico-limbic circuits, An early diagnosis is difficult, but mandatory to prevent the occurrence of devastating familial, marital, professional, socio-economic, medical and medico-legal consequences. Their management is not yet well standardized. Patients and caregivers should be warned about impulse control behaviours before starting dopamine agonists and monitoring for such behaviours while on therapy is requested.

Long-term stability of parameters of antioxidant status in human serum.

The antioxidant status of serum or plasma can be determined using several commercially available assays. Here, four different assays, total antioxidant status (TAS), its second-generation assay (TAS2), biological antioxidant potential (BAP), and enzymatic assay using horseradish peroxidase (EAOC), were applied on human serum samples to test the temperature stability of antioxidants, upon storage of serum for 12 months. The two or three most commonly used temperatures for storage, that is, - 20, - 70 (or - 80), and - 196°C, were selected. The general conclusion is that all assays were stable at the temperatures tested. In addition, there were almost no statistically significant differences between the samples stored at different temperatures. Only the rank order of the EAOC assay was not very good in samples stored at - 20°C. Also three components contributing to the total antioxidant capacity, uric acid, creatinine and bilirubin, showed no statistically significant differences between the temperatures. Therefore, storage at - 20°C is sufficient to maintain a proper assay outcome of most of the total antioxidant assays, although storage at - 70/80°C is to be preferred for longer storage times.

Hand and wrist malpractice claims in The Netherlands: 1993-2008.

We analysed hand and wrist injury and disorder related liability claims in the Netherlands to identify causes and to contribute to the prevention of such claims. Data was collected from 743 hand and wrist claims filed between 1993 and 2007. Consultants were involved in 417 claims (56.1%). Treatment in the emergency department (ED) accounted for 64.9% of these 287 claims involved residents (59.5%). The majority of accepted claims in the ED included treatment by general surgeons (89.2%). The percentage of accepted claims was highest in the general surgery group (26.4%). Of accepted claims in the ED which involved a resident, 93.2% involved a general surgery resident. Better training and supervision is indicated. This paper supports hand injury treatment by adequately trained surgeons and preferably, where possible, by a trained hand surgeon.

Conjugation of nucleosides and oligonucleotides by [3+2] cycloaddition.

A procedure is presented for copper(I)-catalyzed [3+2] cycloaddition of nucleosides and nucleotides in near-quantitative yield. Azido-alkyne cycloaddition was applied for the preparation of a range of adenosine dimers and derivatives with versatile functionality, as well as for the smooth condensation of two oligonucleotide strands. The described technology may find valuable application in the synthesis of oligonucleotide dimers and conjugates.

[Clinical case of the month. Miller-Dieker (lissencephaly) syndrome]. / Le cas clinique du mois. Le syndrome lissencéphalique de Miller-Dieker.

We present the case of a 10-year-old boy who presents with a severe epilepsy resistant to medical treatment in the context of a Miller-Dieker syndrome. This patient underwent the implantation of a pneumogastric nerve stimulator. We describe the patient's clinical history and the main characteristics of lissencephaly syndrome.

Potent antiretroviral therapy initiates normalization of hypergammaglobulinemia and a decline in HIV type 1-specific antibody responses.

Next to a profound T cell immunodeficiency, HIV-1 infection induces activation and dysfunction of B cells, resulting in hypergammaglobulinemia. Whereas T cell immune reconstitution with potent antiretroviral therapy has been extensively documented, limited data are available on B cell immune reconstitution. We studied the effect of potent antiretroviral therapy on antibody titers to the viral proteins gp120 and p24 and on total IgG concentrations. Three retrospectively chosen groups were studied: a successfully treated group, untreated controls, and subjects with virological failure after several months of successful therapy. In the successfully treated group, the median total IgG concentrations normalized, whereas they remained elevated in the untreated group and rebounded after an initial decline in the therapy failure group. The HIV-1-specific antibody titers declined in the successfully treated group and followed the rebound of the HIV RNA levels in the therapy failure group. With potent antiretroviral therapy the hypergammaglobulinemia normalized whereas HIV-1-specific immune responses were weakened. The weakening of antiviral immunity with therapy may be relevant for current attempts to gain immunological control over the virus through structured treatment interruptions or therapeutic vaccinations.

Spin-orbit effects in a GaAs quantum dot in a parallel magnetic field.

We analyze the effects of spin-orbit coupling on fluctuations of the conductance of a quantum dot fabricated in a GaAs heterostructure. Counterintuitively we argue that spin-orbit effects may become important in the presence of a large parallel magnetic field B( parallel), even if they are negligible for B( parallel) = 0. This should be manifest in the level repulsion of a closed dot, and in reduced conductance fluctuations in dots with a small number of open channels in each lead, for large B( parallel). Our picture is consistent with the experimental observations of Folk et al.

Clinical features of inflammatory joint and spine manifestations in Crohn's disease.

167 patients with Crohn's disease were investigated for joint and spine inflammation. Arthritis was observed in 23 patients (14%), sacroiliitis in 24 (14%), and sacroiliitis in combination with arthritis in 11 patients (7%). 15 patients (9%) had ankylosing spondylitis; 9 of them were HLA-B27 positive (60%). A parallel pattern in the course of bowel disease and joint inflammation was observed in 22 out of 34 patients with arthritis (59%). An association between the localization of Crohn's disease and the type of spondylarthritis could not be demonstrated. Patients with arthritis alone developed erythema nodosum (35%) or aphthous stomatitis more often (21%) than patients without spondylarthritis+ (6% and 12%, respectively). Other extra-intestinal manifestations of Crohn's disease did not reveal any association with the development of spondyloarthritis.