Elske T. Massolt

Reproducibility of same session repeated cystometry and pressure-flow studies in women with symptoms of urinary incontinence.

The aim of this study was to determine the reproducibility of same session repeated urodynamic measurements in women with symptoms of urinary incontinence.

Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer

Levothyroxine (LT4) is the standard of care in patients with hypothyroidism. Despite this replacement therapy, quality of life (QoL) remains impaired in a substantial amount of patients. The reasons for this are still a matter of debate. Suggested causes include lack of endogenous T3 secretion by the thyroid, changes in other thyroid hormone metabolites and interference by autoimmune processes.

Prevalence, impact on the quality of life and pathophysiological determinants of nocturia in urinary incontinent women.

The objective of this study was to estimate the prevalence of nocturia in incontinent women in a urogynaecologic practice and its association with the quality of life and to estimate the prevalences of the pathophysiological categories among nocturics. From 1 January 2002, all patients with complaints of urinary incontinence were analysed according to a specific protocol: multichannel urodynamic testing, a 1-h International Incontinence Society (ICS) pad test and a 3-day frequency-volume (FV) chart. From 1 June 2002, subjects had to fill in a standardised quality of life questionnaire as well. Nocturia was defined as two or more micturitions per night calculated from the FV chart. Evaluable FV charts were received from111 patients, and 72 patients completed the questionnaires correctly. The overall prevalence of nocturia was 48.6% (confidence interval: 43.9–53.3%). Nocturia had a negative impact on several aspects of the quality of life. The maximum voided volume was significantly (p=0.005) less in nocturics. The 24-h frequency was higher in nocturics (p=0.001). Nocturics lost more urine during the pad test (p=0.039). The multivariate logistic regression analysis showed that the greater the proportion of 24-h urine excreted at night, the greater the odds of having nocturia and that the lesser the maximum voided volume, the greater the odds of having nocturia. The majority (92.7%) of the nocturics can be classified into one of the responsible pathophysiologic categories: nocturnal polyuria in 51.2%, a low functional bladder capacity in 14.6%, a combination of both in 9.8%, polyuria in 4.9% and a combination of polyuria and nocturnal polyuria in 12.2% of the cases. Nocturia is a frequent symptom among urinary incontinent patients, with a negative impact on several aspects of the quality of life. With a FV chart, nocturics can be classified into one of the responsible pathophysiologic categories in the majority (92.7%) of the cases.

Aberrant levels of hematopoietic/neuronal growth and differentiation factors in euthyroid women at risk for autoimmune thyroid disease

Background Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects. Methods We studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs). We measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7 at baseline. Results BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion. Conclusion Relatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A distinct pattern of four inter correlating immune factors in the relatives preceded TPO-Ab seroconversion in the next 5 years.

Eruptive melanocytic naevi as a sign of primary adrenocortical insufficiency

junction b3 protein (GJB3 or GJB4) have been implicated in EKV. PSEK is characterized by a number of immobile and slowly progressive erythematous keratotic plaques distributed symmetrically over the body. The molecular basis of PSEK has not yet been established. Ishida-Yamamoto et al. reported a mutation in the loricrin (LOR) gene in a Japanese family with PSEK. Cui et al. mapped the disease locus to chromosome 21q, but could not identify any causal gene for the disease within this locus. We report the genetic analysis of two Chinese families with PSEK with autosomal dominant inheritance. This study was approved by the ethics committee of Anhui Medical University and conducted according to the principles of the Declaration of Helsinki. The probands were a 16-year-old girl (III-19) in family 1 (Fig. 1) and a 26-year-old man (III-4) in family 2 (Fig. 2), who both presented with typical characteristics of PSEK. When assessed, 10 affected members (7 male, 3 female) were identified in four generations of family 1 (Fig. 1) and 5 (2 male, 3 female) in three generations of family 2 (Fig. 2). All family members underwent physical examination by experienced clinical dermatologists, and the clinical and histological characteristics supported the diagnosis of PSEK. We assessed the LOR, GJB3 and GJB4 genes, but did not identify any potential mutations that could lead to PSEK. Similar findings were reported previously in a Chinese family and a Turkish family with PSEK. PSEK is inherited in an autosomal dominant manner, with incomplete penetrance and variable expressivity. Previously, a frameshift mutation (709insC) in the LOR gene on 1q21 was identified in a Japanese family with PSEK-like features and mutilating palmoplantar keratoderma (pseudoainhum). Loricrin is a major structural component of the cornified cell envelope of the epidermis. It occurs initially in the granular layer, and participates in the formation of keratohyalin granules. Maestrini idenfied the causative role of the LOR gene in Vohwinkel syndrome (VS). It is possible that our Japanese pedigree might have VS rather than PSEK, because mutilating palmoplantar keratoderma is rare in PSEK. In conclusion, in this study, we found no mutations of LOR, GJB3 and GJB4 in two PSEK families. These and previous results suggest that PSEK is a genetically heterogeneous disorder, and it is likely that more than one genetic locus is responsible for the development of this peculiar disease. Further study, using extensive sequencing of noncoding or regulatory sequence of these genes, is warranted. Acknowledgements

Thyroid State Regulates Gene Expression in Human Whole Blood

Context Despite the well-recognized clinical features resulting from insufficient or excessive thyroid hormone (TH) levels in humans, it is largely unknown which genes are regulated by TH in human tissues. Objective To study the effect of TH on human gene expression profiles in whole blood, mainly consisting of T3 receptor (TR) α-expressing cells. Methods We performed next-generation RNA sequencing on whole blood samples from eight athyroid patients (four females) on and after 4 weeks off levothyroxine replacement. Gene expression changes were analyzed through paired differential expression analysis and confirmed in a validation cohort. Weighted gene coexpression network analysis (WGCNA) was applied to identify thyroid state-related networks. Results We detected 486 differentially expressed genes (fold-change >1.5; multiple testing corrected P value < 0.05), of which 76% were positively and 24% were negatively regulated. Gene ontology (GO) enrichment analysis revealed that three biological processes were significantly overrepresented, of which the process translational elongation showed the highest fold enrichment (7.3-fold, P = 1.8 × 10-6). WGCNA analysis independently identified various gene clusters that correlated with thyroid state. Further GO analysis suggested that thyroid state affects platelet function. Conclusions Changes in thyroid state regulate numerous genes in human whole blood, predominantly TRα-expressing leukocytes. In addition, TH may regulate gene transcripts in platelets.

Serum microRNA profiles in athyroid patients on and off levothyroxine therapy

Background Levothyroxine replacement treatment in hypothyroidism is unable to restore physiological thyroxine and triiodothyronine concentrations in serum and tissues completely. Normal serum thyroid stimulating hormone (TSH) concentrations reflect only pituitary euthyroidism and, therefore, novel biomarkers representing tissue-specific thyroid state are needed. MicroRNAs (miRNAs), small non-coding regulatory RNAs, exhibit tissue-specific expression patterns and can be detectable in serum. Previous studies have demonstrated differential expression of (precursors of) miRNAs in tissues under the influence of thyroid hormone. Objective To study if serum miRNA profiles are changed in different thyroid states. Design and methods We studied 13 athyroid patients (6 males) during TSH suppressive therapy and after 4 weeks of thyroid hormone withdrawal. A magnetic bead capture system was used to isolate 384 defined miRNAs from serum. Subsequently, the TaqMan Array Card 3.0 platform was used for profiling after individual target amplification. Results Mean age of the subjects was 44.0 years (range 20–61 years). Median TSH levels were 88.9 mU/l during levothyroxine withdrawal and 0.006 mU/l during LT4 treatment with a median dosage of 2.1 μg/kg. After normalization to allow inter-sample analysis, a paired analysis did not demonstrate a significant difference in expression of any of the 384 miRNAs analyzed on and off LT4 treatment. Conclusion Although we previously showed an up-regulation of pri-miRNAs 133b and 206 in hypothyroid state in skeletal muscle, the present study does not supply evidence that thyroid state also affects serum miRNAs in humans.

Maternal and obstetrical outcome in 35 cases of well-differentiated thyroid carcinoma during pregnancy

Thyroid cancer, with 6% to 10% of cancer diagnoses, is one of the most common malignancies during pregnancy. Its treatment poses a risk for the pregnancy, as the thyroid gland plays a crucial role in the evolution of pregnancy. The aim of this study is to evaluate treatment of primary well‐differentiated thyroid carcinoma during pregnancy and fetal and maternal outcomes.

Pressure-volume analysis in athyroid patients off and on thyroxine supplementation: a pilot study

Thyroid hormone importantly affects the cardiovascular system. However, evaluation of stroke volume (SV) and its determinants is confounded by variations in volume status that occur along different thyroid states. This study applied the pressure‐volume (PV) framework to obtain relatively load‐independent estimates of cardiac function in hypothyroidism as compared to euthyroidism. Ten athyroid patients were assessed echocardiographically after 4 weeks in deep hypothyroid state, and again after supplementation with oral Levothyroxine (LT4) for 3 months. Thyroid hormone levels were assessed and noninvasive pressure‐volume (PV) analysis based on dedicated repeated echocardiograms was performed. Changes were assessed using paired tests. Results are presented as medians and interquartile ranges. Hypothyroidism was associated with reduced stroke volume (SV: 67.6 ± 17 vs. 75.7 ± 20.6 mL, P = 0.024), preload (end‐diastolic volume, EDV: 122.6 ± 32.5 vs. 135.7 ± 33.6 mL, P = 0.004), and contractility (end‐systolic elastance, Ees: 1.7 ± 0.33 vs. 2.58 ± 1.33 mmHg/mL, P = 0.01). Afterload was constant (effective arterial elastance, Ea: 1.66 ± 0.32 vs. 1.79 ± 0.52 mmHg/mL, P = 0.43) and the total energy spent was lower (PVA∙HR: 86.7 ± 28 vs. 110.9 ± 32.1 J, P = 0.04). Hemodynamic manifestations of frank hypothyroidism in humans are characterized by reduced preload and contractility, and unchanged total afterload. LT4 therapy increased work efficiency and heart rate, but not the net energy expenditure. Noninvasive PV analysis may be useful to follow‐up different thyroid states.

Effects of Thyroid Hormone on Urinary Concentrating Ability

Background: Hypothyroidism has been associated with impaired urinary concentrating ability. However, previous reports on thyroid hormone and urinary concentrating ability in humans only studied a limited number of patients with autoimmune thyroid disease or used healthy controls instead of paired analysis within the same patients. Objective: To study the urinary concentrating ability in athyreotic patients with differentiated thyroid cancer on and off levothyroxine treatment as they are exposed to different thyroid states as part of their treatment in the absence of an autoimmune disease. Design and Methods: We studied 9 patients (mean age of 42.7 years) during severe hypothyroid state (withdrawal of levothyroxine before radioactive iodine therapy) and TSH-suppressed state (on levothyroxine therapy). At these two points, serum and urine samples were collected after 14 h of overnight fasting without any food or drink. Results: Serum and urine osmolality were not significantly different between on and off levothyroxine treatment. Serum creatinine levels were significantly higher in patients off versus on levothyroxine treatment (87.0 vs. 71.0 µmol/L, respectively; p = 0.044) and, correspondingly, the estimated glomerular filtration rate was significantly lower (89.6 vs. 93.1 mL/min, respectively; p = 0.038). Conclusion: Short-term, severe hypothyroidism has no effect on urinary concentrating ability. Our study confirms the well-known effects of thyroid hormone on serum creatinine concentrations.