Premature ovarian insufficiency and autoimmune profiles: a prospective case-control study.

OBJECTIVE: Autoimmunity seems to be present in a large proportion of women with spontaneous premature ovarian insufficiency (POI). Whether these women are at increased risk for autoimmune disease has not been determined to date. Therefore, the aim of this study was to investigate a large series of antibodies in order to shed more light into the autoimmune risk of POI women. METHODS: In a prospective case-control study, blood samples from 66 patients with spontaneous POI and 66 healthy controls were analyzed for a series of autoimmune antibodies. RESULTS: POI women revealed significantly increased thyroglobulin antibodies (TGAb) (p = 0.045) and thyroid peroxidase antibodies (TPOAb) (p = 0.002). At least one abnormal autoimmune parameter was present in 37.9% of POI women, compared to 18.2% in healthy controls (p = 0.045). A strong association between POI and increased TGAb (adjusted odds ratio 3.586, p = 0.028), increased TPOAb (adjusted odds ratio 7.496, p = 0.003) and any increased autoimmune parameter (adjusted odds ratio 3.189, p = 0.008) could be demonstrated in a binary logistic regression model. CONCLUSION: A high prevalence of autoimmunity in POI women compared to a healthy young collective could be demonstrated. Thyroid antibodies were significantly increased in POI women. Our data highlight the increased risk for autoimmune diseases, especially for thyroid disorders.

User preferences for a mobile application to report adverse events following vaccination.

The passive surveillance system is an important tool in pharmacovigilance of vaccines. However, reporting of adverse events following immunization (AEFI) post-marketing has limitations regarding under-reporting, biased reports and lack of exposure data resulting in imprecise estimates. New mobile application technology may provide an opportunity for an enhanced surveillance. A pre-requisite for the use of new app-based technology is to identify practical challenges and end users' preferences for design of app-features. The objectives were (i) to investigate the recruitment and feasibility of an app-based study in Germany, (ii) to assess individuals' motivation to participate in such a study and (iii) to identify app-features for reporting AEFI. We conducted a cross-sectional study among employees of a financial institution who attended the occupational health office during the seasonal influenza vaccination in November 2017. Participants tested feasibility and assessed an app prototype for AEFI reporting by using a case vignette and a questionnaire. Of the 153 attending employees, 65 (42%) agreed to participate and returned the questionnaire. Twenty-three (63%) rated the experience of reporting AEFI with the app prototype to be positive. Among three features offered for gamification, collecting points was most frequently chosen (n=22, 34%). The main reason for declining participation was the apprehension about data protection (n=28, 43%). Results suggest that the app-based technology was well accepted and is a suitable supplement for AEFI reporting and in our study. A convincing data protection concept is likely to enhance acceptability of such a system.

Sex- and age patterns in incidence of infectious diseases in Germany: analyses of surveillance records over a 13-year period (2001-2013).

Sex differences in the incidence of infections may indicate different risk factors and behaviour but have not been analysed across pathogens. Based on 3.96 million records of 33 pathogens in Germany, notified from 2001 to 2013, we applied Poisson regression to generate age-standardised incidence rate ratios and assessed their distribution across age and sex. The following trends became apparent: (a) pathogens with male incidence preponderance at infant and child age (meningococcal disease (incidence rate ratio (IRR) = 1.19, 95% CI 1.03-1.38, age = 0-4); influenza (IRR = 1.09, 95% CI 1.06-1.13, age = 0-4)), (b) pathogens with sex-switch in incidence preponderance at puberty (e.g. norovirus (IRR = 1.10, 95% CI 1.02-1.19 in age = 5-14, IRR = 0.96, 95% CI 0.93-0.99, age ⩾ 60), (c) pathogens with general male incidence preponderance (bacterial/parasitic infections with campylobacter, Yersinia and Giardia), (d) pathogens with male incidence preponderance at juvenile and adult age (sexually transmitted or vector-borne infections (combined-IRR = 2.53, 95% CI 2.36-2.71, age = 15-59), (e) pathogens with male preponderance at older age (tick-borne encephalitis - IRR = 2.75, 95% CI 1.21-6.24, listeriosis - IRR = 2.06, 95% CI 1.38-3.06, age ⩾ 60). Risk factor concepts only partly serve to interpret similarities of grouped infections, i.e. transmission-related explanations and sex-specific exposures not consistently explain the pattern of food-borne infections (b). Sex-specific differences in infectious disease incidence are well acknowledged regarding the sexually transmitted diseases. This has led to designing gender-specific prevention strategies. Our data suggest that for infections with other transmission routes, gender-specific approaches can also be of benefit and importance.

Fast and reliable method to estimate losses of single-mode waveguides with an arbitrary 2D trajectory.

Photonic wire bonds, i.e., freeform waveguides written by 3D direct laser writing, emerge as a technology to connect different optical chips in fully integrated photonic devices. With the long-term vision of scaling up this technology to a large-scale fabrication process, the in situ optimization of the trajectory of photonic wire bonds is at stake. A prerequisite for the real-time optimization is the availability of a fast loss estimator for single-mode waveguides of arbitrary trajectory. Losses occur because of the bending of the waveguides and at transitions among sections of the waveguide with different curvatures. Here, we present an approach that resides on the fundamental mode approximation, i.e., the assumption that the photonic wire bonds predominantly carry their energy in a single mode. It allows us to predict in a quick and reliable way the pertinent losses from pre-computed modal properties of the waveguide, enabling fast design of optimum paths.

Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis.

OBJECTIVE: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families. METHODS: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family. RESULTS: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele. CONCLUSION: A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.

Heritability and familiality of neurological soft signs: evidence from healthy twins, patients with schizophrenia and non-psychotic first-degree relatives.

BACKGROUND: Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study examined the heritability and familiality of NSS in healthy twins and patient-relative pairs. METHOD: The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives. RESULTS: NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS. CONCLUSIONS: Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.

Prospective evaluation of the learning curve of fertiloscopy with and without ovarian drilling.

Fertiloscopy represents an alternative to laparoscopy in the diagnostic evaluation of unexplained infertility or for the purpose of ovarian drilling. The learning curve of fertiloscopy in an experienced laparoscopic surgeon was evaluated in a prospective multicentre observational trial. A total of 110 fertiloscopies were carried out. At Centre 1, a beginner, and at Centre 2, an expert in fertiloscopy, performed the procedures. In three cases in Centre 1, and in 0 cases in Centre 2, the procedure was converted to transabdominal laparoscopy owing to intraoperative complications. Median operating time was longer at Centre 1 during the first 40 procedures (P < 0.001) and equal thereafter. Analyzing fertiloscopies with and without ovarian drilling separately, operating time was only longer for the first 20 procedures in each group (P < 0.001 and P = 0.002). In a multivariate analysis, intraoperative complications and fertiloscopy with ovarian drilling (compared with diagnostic fertiloscopy) were associated with longer duration of surgery (P < 0.001 for both parameters). An increasing consecutive number of fertiloscopies was associated with shorter duration of surgery (P < 0.001). Experienced laparoscopists should consider a transition towards fertiloscopy in the diagnostic workup of unexplained infertility or for the purpose of ovarian drilling.

Interspecific patterns of phenotypic selection do not predict intraspecific patterns.

We estimated linear (ß) and nonlinear (γ) selection gradients to quantify host plant-mediated selection on the trait gall size in each of 22 unequally sampled subpopulations of the cynipid gall wasp Belonocnema treatae. We characterized the relationship between variation in subpopulation sample size and the magnitude of and the variance among selection gradients. We then tested the hypothesis that the intraspecific patterns we observed would follow two patterns that have emerged from published estimates of linear and nonlinear selection gradients compiled across species, namely that the average magnitude of ß and γ and the variance among estimated ß and γ decrease with increasing sample size. For both ß and γ, intraspecific patterns of phenotypic selection in relation to sample size were not predicted by interspecific patterns. Thus, our results suggest that when selection is heterogeneous among subpopulations, variation in the biological basis for selection is more important in influencing estimates of selection than is variation in study size. Our study highlights the value of inspecting selection in relation to sampling effort at the level at which understanding the sources of variation in selection is most important, among populations within species.

Sequential cervical length screening in pregnancies after loop excision of the transformation zone conisation: a retrospective analysis.

OBJECTIVE: To review our experience with a screening programme that included four sequential cervical length (CL) measurements from 16 to 22( ) weeks of gestation. DESIGN: Historical cohort study. SETTING: Tertiary-care centre in a university hospital. POPULATION: There were 312 singleton pregnancies in 321 women with a previous large loop excision of the transformation zone (LLETZ), and 62 pregnancies after a second-trimester miscarriage in a previous pregnancy. METHODS: The CL measurements were performed by transvaginal ultrasound at 16, 18, 20, and 22 completed weeks of gestation. MAIN OUTCOME MEASURES: Early preterm delivery before 34 completed weeks of gestation. RESULTS: Early preterm delivery was found in 7.4%. The CL at 16 completed weeks of gestation was smaller in the LLETZ group (36 mm, interquartile range 30-40 mm) compared with the control group (38 mm, interquartile range 32-42 mm; P = 0.040). For the analysis of risk factors for early preterm delivery after LLETZ, only cases with a complete data set were included (n = 145). In a multivariate analysis, two parameters remained significantly predictive, with CL at 16 completed weeks of gestation being the most significant measure (P < 0.001, OR 0.90, 95% CI 0.83-0.98), followed by conception using IVF treatment (P = 0.031, OR 0.64, 95% CI 1.54-34.80). CONCLUSIONS: Even as early as 16 weeks of gestation, women with early preterm delivery reveal a significantly lower CL than those without. Dynamics in the CL do not add to this information.

Dehydroepiandrosterone in women with premature ovarian failure and Hashimoto's thyroiditis.

We evaluated dehydroepiandrosterone sulfate (DHEAS) levels in premature ovarian failure (POF) patients with and without Hashimoto's thyroiditis, and the impact of DHEA supplementation on thyroid autoantibodies. In a retrospective case series, we included 67 women with spontaneous POF who received estrogen/gestagen replacement with or without DHEA (30 mg/day) for 3 months. Women who were seropositive for thyroglobulin antibodies and/or thyroperoxidase autoantibodies (n = 30) revealed lower pretherapeutic DHEAS levels (1.2 µg/ml, range 0.4-2.9 µg/ml vs. 1.9 µg/ml, range 0.2-3.9 µg/ml; p < 0.001). DHEAS showed an inverse correlation with both thyroglobulin antibodies (r = -0.426, p < 0.001) and thyroperoxidase autoantibodies (r = -0.362, p = 0.002). When treated with additional DHEA, significant decreases were found for thyroperoxidase autoantibodies (median 85.0 IU/ml, range 41-600 IU/ml vs. median 51.0 IU/ml, range 20-589 IU/ml; p = 0.005) but not for thyroglobulin antibodies.

Schmidt decompositions of parametric processes II: vector four-wave mixing.

In vector four-wave mixing, one or two strong pump waves drive two weak signal and idler waves, each of which has two polarization components. In this paper, vector four-wave mixing processes in a randomly-birefringent fiber (modulation interaction, phase conjugation and Bragg scattering) are studied in detail. For each process, the Schmidt decompositions of the coupling matrices facilitate the solution of the signal-idler equations and the Schmidt decomposition of the associated transfer matrix. The results of this paper are valid for arbitrary pump polarizations.

Prenatal sonography can predict degree of placental invasion.

OBJECTIVE: To evaluate whether the maximum degree of placental invasion (placenta accreta, increta or percreta) can be predicted with ultrasound imaging, using criteria developed in our department. METHODS: This was a retrospective study of all 232 patients at risk for placental invasion who were part of a routine screening program for placental invasion from January 2001 to January 2011. The whole placenta was scanned in a systematic manner using both gray-scale ultrasound and color-flow mapping. Sonographic findings were compared with the clinical outcome during and after delivery and the histomorphological examination of the placenta. RESULTS: Placental invasion was suspected by ultrasound in 40 (17.2%) patients and was clinically/histopathologically confirmed in a total of 35 (15.1%) patients. The sensitivity, specificity and positive and negative predictive values of ultrasound for placental invasion were 91.4% (95% CI, 77.6-97.0%), 95.9% (95% CI, 92.2-97.9%), 80.0% (95% CI, 65.2-89.5%) and 98.4% (95% CI, 95.5-99.5%), respectively. No case of placenta increta (n = 7) or percreta (n = 17) was diagnosed as showing normal placentation or placenta accreta on ultrasound, giving an overall accuracy for the differentiation between normal placentation/placenta accreta and placenta increta/percreta of 100%. CONCLUSION: Our data suggest that prediction of the degree of placental invasion is possible using prenatal ultrasound, with high overall accuracy.

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa.

The RP14 autosomal recessive Retinitis pigmentosa (arRP) locus has been mapped to a 2cM region of chromosome 6p21.3. TULP1 (the gene encoding tubby-like protein 1) is a candidate target for the disease mutation because it maps to the RP14 minimum genetic region and because a mutation in the highly homologous mouse tub gene leads to obesity, deafness and early progressive retinal degeneration. Here we report a splice-site mutation (IVS14+1, G-->A) that is homozygous in all affected individuals (N=33) and heterozygous in all obligate carriers (N=50) from two RP14-linked kindreds. The mutation was not observed in 210 unrelated controls. The data indicate that impairment of TULP1 protein function is a rare cause of arRP and that the normal protein plays an essential role in the physiology of the retina.

A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish.

The most characteristic features of bipolar affective disorder (manic-depressive illness) are episodes of mania (bipolar I, BPI) or hypomania (bipolar II, BPII) interspersed with periods of depression. Manic-depressive illness afflicts about one percent of the population, and if untreated, is associated with an approximately 20% risk of suicide. Twin, family and adoption studies provide compelling evidence for a partial genetic aetiology, but the mode(s) of inheritance has not been identified. Nonetheless, the majority of genetic linkage studies have assumed classical mendelian inheritance attributable to a single major gene. Although segregation analyses have yielded inconsistent results (with most studies rejecting a single locus inheritance model), the best single gene model is dominant inheritance if only BPI is considered. Reported linkages of bipolar affective disorder on chromosomes 11, 18, 21 and X have been difficult to substantiate, and additional studies are required for replication or exclusion of these regions. We now present the results of our genome-wide linkage analyses that provide evidence that regions on chromosomes 6, 13 and 15 harbour susceptibility loci for bipolar affective disorder, suggesting that bipolar affective disorder in the Old Order Amish is inherited as a complex trait.

Risk factors for postoperative bleeding after thyroid surgery.

BACKGROUND: Postoperative bleeding after thyroid surgery is a feared and life-threatening complication. The aim of the study was to identify risk factors for postoperative bleeding, with special emphasis on the impact of the individual surgeon and the time to diagnosis of the complication. METHODS: Data on consecutive thyroid operations were collected prospectively in a database over 30 years and analysed retrospectively for potential risk factors for postoperative bleeding. RESULTS: There were 30,142 operations and postoperative bleeding occurred in 519 patients (1·7 per cent). Risk factors identified were older age (odds ratio (OR) 1·03 per year), male sex (OR 1·64), extent of resection (OR up to 1·41), bilateral procedure (OR 1·99) and operation for recurrent disease (OR 1·54). The risk of complications among individual surgeons differed by up to sevenfold. Postoperative bleeding occurred in 336 (80·6 per cent) of 417 patients within the first 6 h after surgery. Postoperative bleeding was diagnosed after 24 h in ten patients (2·4 per cent), all of whom had bilateral procedures. Nine patients required urgent tracheostomy. Three patients died, giving a mortality rate of 0·01 per cent overall and 0·6 per cent among patients who had surgery for postoperative bleeding. CONCLUSION: Observation for up to 24 h is recommended for the majority of patients undergoing bilateral thyroid surgery in an endemic goitre area. Same-day discharge is feasible in selected patients, especially after a unilateral procedure. Quality improvement by continuous outcome monitoring and retraining of individual surgeons is suggested.

Impact of Doppler sonography on intrauterine management and neonatal outcome in preterm fetuses with intrauterine growth restriction.

OBJECTIVES: To test the hypothesis that earlier delivery may be warranted to improve neonatal outcome of fetuses with intrauterine growth restriction (IUGR) with abnormal Doppler parameters. METHODS: This was a retrospective cohort study of 110 fetuses with an antenatal diagnosis of IUGR due to placental insufficiency which had a very low birth weight (< 1500 g), delivered at the Department of Fetomaternal Medicine of the Medical University of Vienna, Austria, between January 1999 and July 2009. Doppler results before delivery were classified as follows: Group 1: abnormal umbilical artery (UA) pulsatility index (PI) more than 2 SD above the mean for normal reference data, or absent UA end-diastolic flow, both with normal middle cerebral artery (MCA) PI (mean ± 2 SD); Group 2: abnormal UA-PI > mean + 2 SD, or absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and normal ductus venosus (DV) PI (mean ± 2 SD); Group 3: absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and abnormal DV-PI (> mean + 2 SD) and/or absent or reversed end-diastolic DV flow. Pregnancy outcome was analyzed according to Doppler results. RESULTS: Due to very poor prognosis, 19 fetuses underwent expectant management and died in utero. These were excluded from further analyses. Of the remaining 91 cases, 17 were in Doppler Group 1, 44 in Group 2 and 30 in Group 3. Within 4 weeks after delivery, 0/17 (0%) infants in Group 1 died, 2/44 (4.5%) infants in Group 2 died and 7/30 (23.3%) infants in Group 3 died (P = 0.019). None of the 42 Group 2 cases that delivered at or after 28 completed gestational weeks died within 4 weeks after delivery, in contrast to 4/20 (20.0%) Group 3 cases (P = 0.009). In comparison, among infants delivered before 27 completed gestational weeks, 2/2 (100%) Group 2 cases died and 3/10 (30.0%) Group 3 cases died; P = 0.152). CONCLUSIONS: Doppler examinations are highly predictive in assessing the outcome of IUGR fetuses. From 28 completed gestational weeks, early delivery before the onset of fetal cardiac decompensation might be beneficial.

Heavy metals as risk factors for human diseases - a Bayesian network approach.

Modern industrial agricultural processes expose human beings to multifactorial environmental pollution including heightened levels of heavy metals. The effects of acute heavy metal exposures at toxic levels are usually known; they are tested for and treated promptly. The effects of low/moderate-level chronic heavy metal exposures are less known as they may be subclinical, and pathogenic effects may only manifest clinically over time under the disguise of a diagnosable disease or miscellaneous symptoms attributed to aging. Consequently, the health impact of low-moderate heavy metal exposure is unlikely to be identified. Furthermore, established heavy metal safety levels often fail to recognize the potential toxic effects on humans. We report in this review what is known about the sub-chronic and chronic effects of exposure to heavy metals, particularly lead, mercury, cadmium, arsenic, and nickel, and we highlight their possible effects in the brain, cardiovascular and endocrine-metabolic systems, and on reproduction.

Diffusion and interaction dynamics of the cytosolic peroxisomal import receptor PEX5.

Cellular functions rely on proper actions of organelles such as peroxisomes. These organelles rely on the import of proteins from the cytosol. The peroxisomal import receptor PEX5 takes up target proteins in the cytosol and transports them to the peroxisomal matrix. However, its cytosolic molecular interactions have so far not directly been disclosed. Here, we combined advanced optical microscopy and spectroscopy techniques such as fluorescence correlation spectroscopy and stimulated emission depletion microscopy with biochemical tools to present a detailed characterization of the cytosolic diffusion and interaction dynamics of PEX5. Among other features, we highlight a slow diffusion of PEX5, independent of aggregation or target binding, but associated with cytosolic interaction partners via its N-terminal domain. This sheds new light on the functionality of the receptor in the cytosol as well as highlighting the potential of using complementary microscopy tools to decipher molecular interactions in the cytosol by studying their diffusion dynamics.

Full and semi-analytic analyses of two-pump parametric amplification with pump depletion.

This paper solves the four coupled equations describing non-degenerate four-wave mixing, with the focus on amplifying a signal in a fiber optical parametric amplifier (FOPA). Based on the full analytic solution, a simple approximate solution describing the gain is developed. The advantage of this new approximation is that it includes the depletion of the pumps, which is lacking in the usual quasi-linearized approximation. With the proposed model it is thus simple to predict the gain of a FOPA, which we demonstrate with a highly nonlinear fiber to show that an undepleted FOPA can produce a flat gain spectrum with a bandwidth in the 100-nm range, centered on the zero-dispersion wavelength. When running the FOPA in depletion, this range can be slightly increased.