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The genetic causes underlying incontinence in both children and adults have begun to be unravelled during the last decades. The aim of this scoping review is to synthesize current knowledge on the genetics of childhood and adult urinary and faecal incontinence, identify similarities between different incontinence subgroups, and identify knowledge gaps to aid future research. PRISMA-ScR was used, and 76 studies were included. Early epidemiological family and twin studies suggest high heritability of incontinence. Linkage studies provide evidence for the existence of rare genetic variants; however, these variants have not been identified. Later candidate gene association studies and recent genome-wide association studies provide the first preliminary evidence that common risk variants also play a role. The genetics of incontinence in children and adults has predominantly been studied separately, but this review identifies for the first time the endothelin system as a potential common pathophysiological pathway. Overall, these findings strengthen the hypothesis that genetic variants play a prominent role in the pathogenesis of incontinence. Future research should include hypothesis-free studies of rare and common variants in large well-characterized cohorts with incontinence. Studies should include different age groups and ethnicities and both sexes to fully reveal the genetics of incontinence., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Gestational diabetes mellitus (GDM) is recognized as a "window of opportunity" for the future prediction of such complications as type 2 diabetes mellitus and pelvic floor muscle disorders, including urinary incontinence and genitourinary dysfunction. Translational studies have reported that pelvic floor muscle disorders are due to a GDM-induced-myopathy (GDiM) of the pelvic floor muscle and rectus abdominis muscle (RAM). We now describe the transcriptome profiling of the RAM obtained by Cesarean section from GDM and non-GDM women with and without pregnancy-specific urinary incontinence (PSUI). We identified 650 genes in total, and the differentially expressed genes were defined by comparing three control groups to the GDM with PSUI group (GDiM). Enrichment analysis showed that GDM with PSUI was associated with decreased gene expression related to muscle structure and muscle protein synthesis, the reduced ability of muscle fibers to ameliorate muscle damage, and the altered the maintenance and generation of energy through glycogenesis. Potential genetic muscle biomarkers were validated by RT-PCR, and their relationship to the pathophysiology of the disease was verified. These findings help elucidate the molecular mechanisms of GDiM and will promote the development of innovative interventions to prevent and treat complications such as post-GDM urinary incontinence.

The mechanisms that link visceral mechanosensation to the perception of internal organ status (i.e., interoception) remain elusive. In response to bladder filling, the urothelium releases ATP, which is hypothesized to stimulate voiding function by communicating the degree of bladder fullness to subjacent tissues, including afferent nerve fibers. To determine if PIEZO channels function as mechanosensors in these events, we generated conditional urothelial Piezo1-, Piezo2-, and dual Piezo1/2-knockout (KO) mice. While functional PIEZO1 channels were expressed in all urothelial cell layers, Piezo1-KO mice had a limited phenotype. Piezo2 expression was limited to a small subset of superficial umbrella cells, yet male Piezo2-KO mice exhibited incontinence (i.e., leakage) when their voiding behavior was monitored during their active dark phase. Dual Piezo1/2-KO mice had the most affected phenotype, characterized by decreased urothelial responses to mechanical stimulation, diminished ATP release, bladder hypoactivity in anesthetized Piezo1/2-KO females but not males, and urinary incontinence in both male and female Piezo1/2-KO mice during their dark phase but not inactive light one. Our studies reveal that the urothelium functions in a sex- and circadian rhythm-dependent manner to link urothelial PIEZO1/2 channel-driven mechanotransduction to normal voiding function and behavior, and in the absence of these signals, bladder dysfunction ensues.

Purpose: Urinary incontinence and fecal incontinence are common disorders in women that negatively impact quality of life. In addition to known health and lifestyle risk factors, genetics may have a role in continence. Identification of genetic variants associated with urinary incontinence and fecal incontinence could result in a better understanding of etiologic pathways, and new interventions and treatments., Materials and Methods: We previously generated genome-wide single nucleotide polymorphism data from Nurses' Health Studies participants. The participants provided longitudinal urinary incontinence and fecal incontinence information via questionnaires. Cases of urinary incontinence (6,120) had at least weekly urinary incontinence reported on a majority of questionnaires (3 or 4 across 12 to 16 years) while controls (4,811) consistently had little to no urinary incontinence reported. We classified cases of urinary incontinence in women into stress (1,809), urgency (1,942) and mixed (2,036) subtypes. Cases of fecal incontinence (4,247) had at least monthly fecal incontinence reported on a majority of questionnaires while controls (11,634) consistently had no fecal incontinence reported. We performed a genome-wide association study for each incontinence outcome., Results: We identified 8 single nucleotide polymorphisms significantly associated (p <5×10 -8 ) with urinary incontinence located in 2 loci, chromosomes 8q23.3 and 1p32.2. There were no genome-wide significant findings for the urinary incontinence subtype analyses. However, the significant associations for overall urinary incontinence were stronger for the urgency and mixed subtypes than for stress. While no single nucleotide polymorphism reached genome-wide significance for fecal incontinence, 4 single nucleotide polymorphisms had p <10 -6 ., Conclusions: Few studies have collected genetic data and detailed urinary incontinence and fecal incontinence information. This genome-wide association study provides initial evidence of genetic associations for urinary incontinence and merits further research to replicate our findings and identify additional risk variants.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The purpose of this paper was to investigate the effects and mechanism of polysaccharide (PAOF) from Alpiniae oxyphyllae fructus on urinary incontinence (UI) in old-age hydruric model rats (OHMR). Results suggested that PAOF can significantly reduce the urination volume, Na + , Cl - emission and increase K + excretion of OHMR. In addition, PAOF can increase the content of aldosterone (ALD) and antidiuretic hormone (ADH) in blood of OHMR. The coefficients of spleen, thymus and adrenal of OHMR were improved by PAOF. Furthermore, PAOF can not only elevate significantly the expression of β3-adrenoceptor mRNA in bladder detrusor of OHMR, but also increase the content of adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in bladder detrusor of OHMR. Meanwhile, PAOF can elevate significantly the expression of PKA protein in bladder detrusor of rats with polyuria. The data implied that PAOF may offer therapeutic potential against UI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Enuresis can cause loss of self-esteem in children, change relations with family and friends, and decrease the school success. This study was conducted to determine the prevalence of urinary incontinence (UI) in school children aged between 11-14 years and identify the emotions and social problems of enuretic children., Materials and Methods: A mixed methods approach was used on a group of students who reported UI by combining quantitative data from school population-based cross-sectional design with qualitative data using in-depth interview techniques. The data of this descriptive and cross-sectional study were collected from 2750 primary school students aged between 11-14 years in Istanbul., Results: The overall prevalence of UI was 8.6% and decreased with age. Prevalence of the diurnal enuresis in children was 67.9% and all of them had non-monosymptomatic enuresis. 83.3% of the children were identifiedwith secondary enuresis for 1-3 years. UI was significantly more common in boys and those who had frequent urinary infections, whose first degree relatives had urinary incontinence problem in childhood, and who reportedlow socioeconomic level in the family. The emotional and social effects of urinary incontinence were given in the context of children's own expressions., Conclusion: Urinary incontinence is an important problem of school-age children. In this study the prevalence of UI was found to be 8.6%, diurnal UI and secondary enuresis were very common, and all of the children werenon-monosymptomatic. Enuresis has negative emotional and social effects on children.

The capacity to store urine and initiate voiding is a valued characteristic of the human urinary bladder. To maintain this feature, it is necessary that the bladder can sense when it is full and when it is time to void. The bladder has a specialized epithelium called urothelium that is believed to be important for its sensory function. It has been suggested that autocrine ATP signalling contributes to this sensory function of the urothelium. There is well-established evidence that ATP is released via vesicular exocytosis as well as by pannexin hemichannels upon mechanical stimulation. However, there are still many details that need elucidation and therefore there is a need for the development of new tools to further explore this fascinating field. In this work, we use new microphysiological systems to study mechanostimulation at a cellular level: a mechanostimulation microchip and a silicone-based cell stretcher. Using these tools, we show that ATP is released upon cell stretching and that extracellular ATP contributes to a major part of Ca 2+ signalling induced by stretching in T24 cells. These results contribute to the increasing body of evidence for ATP signalling as an important component for the sensory function of urothelial cells. This encourages the development of drugs targeting P2 receptors to relieve suffering from overactive bladder disorder and incontinence., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Relevance: Collagen type I and III have a significant role in the development of pelvic organ prolapse (POP) and urinary incontinence in women. The role of the COL3A1 gene polymorphism remains debatable. Some studies and meta-analyzes have found a direct correlation between genetic defects and POP, while other researchers have not confirmed this association. This study aimed to investigate the association of the 1800255 COL3A1 gene polymorphism with the development of POP and urinary incontinence in women., Materials and Methods: The study group comprised 52 patients (mean age 64.4 years) with verified POP and stress urinary incontinence. The control group included 21 patients without pelvic floor dysfunction. Patients were comparable in age and had at least one or more risk factors for developing pelvic floor dysfunction. Exclusion criteria for both groups were Marfan and Ehlers-Danlos syndromes and a history of surgery for POP or incontinence (for the control group). In all women, saliva samples were collected to detect polymorphism at the rs1800255 locus of the COL3A1 gene. Genotyping was conducted by Sanger sequencing., Results: In patients with isolated genital prolapse, homozygous polymorphism (AA) had a low sensitivity (0.06) but an extremely high specificity (0.95). Heterozygote (GA) had the sensitivity of 0.35, the specificity of 0.53, and the AUC of 0.44. For urinary incontinence by homozygote (AA), sensitivity was 0.08, specificity 0.96, and by heterozygote (GA) 0.45 and 0.63, respectively. For the combination of pelvic prolapse and urinary incontinence by homozygote (AA), sensitivity was 0.07, specificity 1.0, and heterozygote (GA) 0.41 and 0.62, respectively., Conclusion: Given the high specificity of the polymorphism at the rs1800255 locus of the COL3A1 gene, determined by the Sanger sequencing, it can be concluded that there is an association between this polymorphism and urinary incontinence and POP in women.

Aims: To characterize the urinary incontinence observed in adult Gli2 +/ - ; Gli3 Δ699/+ female mice and identify the defects underlying the condition., Methods: Gli2 +/ - and Gli3 Δ699/+ mice were crossed to generate: wild-type, mutant Gli2 (Gli2 +/- ), mutant Gli3 (Gli3 Δ699/+ ), and double mutant (Gli2 +/- ; Gli3 Δ699/+ ) female mice, verified via Polymerase Chain Reactions. Bladder functional studies including cystometrogram (CMG), leak point pressure (LPP), and voiding testing were performed on adult female mice. Female bladders and urethras were also analyzed via ink injection and histological assays., Results: CMG tracing showed no signal corresponding to the filling of the Gli2 +/- ; Gli3 Δ699/+ bladders. LPP were significantly reduced in Gli2 +/- ; Gli3 Δ699/+ mice compared to wild-type mice. CMG studies revealed a decrease in peak micturition pressure values in Gli2 +/- ; Gli3 Δ699/+ mice compared with all other groups. No significant differences between mutant and wild-type mice were detected in urinary output. Histological analyses revealed Gli2 +/- ; Gli3 Δ699/+ mice exhibited a widened urethra and a decrease in smooth muscle layer thickness in the bladder outlet and urethra, with increased mucosal folding., Conclusions: Gli2 +/ - ; Gli3 Δ699/+ adult female mice display persistent urinary incontinence due to the malformation of the bladder outlet and urethra. This presents a consistent and reliable genetic mouse model for female urinary incontinence and alludes to the key role of genetic factors involved in the condition., (© 2017 Wiley Periodicals, Inc.)

Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros -/- ) mice show defects in motor functions and die before 6 months of age. Nrros -/- mice display astrogliosis and lack normal CD11b hi CD45 lo microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros -/- CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.

A 4-year-old boy was referred to the nephrologist with daytime urinary incontinence and suspicion of an overactive bladder. At the age of 17 months he had been referred to the pediatric endocrinologist because of polyuria and polydipsia in order to exclude diabetes insipidus. Repeated water deprivation tests and a magnetic resonance imaging scan of the brain were normal. Diabetes insipidus was excluded, and primary polydipsia was thought to be most likely since diabetes mellitus also had been excluded. At the current presentation, he drank up to 3 L a day and quite often had wet diapers. He also seemed to pass stools infrequently and with difficulty. Curiously his grandmother had similar symptoms of polyuria and polydipsia since childhood and had been diagnosed with primary polydipsia. The physical examination of our pediatric patient was normal. In the differential diagnosis we included diabetes insipidus but also contemplated other possibilities, such as nephronophthisis, tubulopathies and hypercalciuria. Laboratory results including urinalysis and an ultrasound of the kidney did not show any abnormalities, making a tubulopathy or hypercalciuria unlikely. A desmopressin test by the intravenous route came back completely normal, pointing to another cause than diabetes insipidus. Genetic testing for the nephronophthisis came back negative but was positive for a missense mutation in the AVPR2 gene (p.Arg104Cys) associated with partial nephrogenic diabetes insipidus. He was started on daily desmopressin. Within 3 days the urinary incontinence resolved as did the polyuria and faecal incontinence. His grandmother was referred to the geneticist and eventually the adult nephrologist. This case highlights the importance of being thorough when confronted with a difficult diagnosis. It also emphasizes that a test result does not necessarily equate to the presence or absence of a condition since the test with 100 % sensitivity and specificity has yet to be discovered.

Background: Pelvic floor dysfunction (PFD) is a group of clinical conditions including stress urinary incontinence (SUI) and pelvic organ prolapse (POP). The abnormality of collagen and elastin metabolism in pelvic connective tissues is implicated in SUI and POP., Methods: To reconstitute the connective tissues with normal distribution of collagen and elastin, we transduced elastin to bone marrow-derived mesenchymal stem cells (BMSC). Elastin-expressing BMSCs were then differentiated to fibroblasts using bFGF, which produced collagen and elastin. To achieve the sustained release of bFGF, we formulated bFGF in poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP)., Results: In an in vitro cell culture system of 7 days, when no additional bFGF was administrated, the initial PLGA-loaded bFGF NP induced prolonged production of collagen and elastin from elastin-expressing BMSCs. In vivo, co-injection of PLGA-loaded bFGF NP and elastin-expressing BMSCs into the PFD rats significantly improved the outcome of urodynamic tests. Together, these results provided an efficient model of connective tissue engineering using BMSC and injectable PLGA-loaded growth factors., Conclusions: Our results provided the first instance of a multidisciplinary approach, combining both stem cell and nanoparticle technologies, for the treatment of PFD.

Purpose of Investigation: The authors studied whether family history of urinary incontinence (UI) is associated with pre- and postpartum UI., Materials and Methods: In 2010, Dutch postpartum women at three months were approached to fill in a Web-based questionnaire on UI and risk factors (body mass index, BMI), parity, pelvic organ prolapse, and family history. Results were analyzed with Chi-square and logistic regression analyses., Results: 162 (61%) questionnaires were analyzed, 76 (47%) women reported UI before, during and/or after pregnancy, of which 34% also reported a UI family history. Sixteen (19%) out of 84 women without UI reported UI family history (p = 0.05). BMI was associated with prepartum UI (p = 0.035), but the association disappears when adding family history. Women with unknown UI family history had higher risk for postpartum U., Conclusion: UI family history is associated with UI during pregnancy. More awareness and research is needed whether adding family history questions on UI in prepartum consultations improves timely prevention.

Here we show that male, but not female mice lacking expression of the GTPase M-Ras developed urinary retention with distention of the bladder that exacerbated with age but occurred in the absence of obvious anatomical outlet obstruction. There were changes in detrusor morphology in Mras-/- males: Smooth muscle tissue, which exhibited a compact organization in WT mice, appeared disorganized and became increasingly 'layered' with age in Mras-/- males, but was not fibrotic. Bladder tissue near the apex of bladders of Mras-/- males exhibited hypercontractility in response to the cholinergic agonist carbachol in in vitro, while responses in Mras-/- females were normal. In addition, spontaneous phasic contractions of detrusors from Mras-/- males were increased, and Mras-/- males exhibited urinary incontinence. We found that expression of the muscarinic M2 and M3 receptors that mediate the cholinergic contractile stimuli of the detrusor muscle was dysregulated in both Mras-/- males and females, although only males exhibited a urinary phenotype. Elevated expression of M2R in young males lacking M-Ras and failure to upregulate M3R with age resulted in significantly lower ratios of M3R/M2R expression that correlated with the bladder abnormalities. Our data suggests that M-Ras and M3R are functionally linked and that M-Ras is an important regulator of male bladder control in mice. Our observations also support the notion that bladder control is sexually dimorphic and is regulated through mechanisms that are largely independent of acetylcholine signaling in female mice.

Neurogenic lower urinary tract dysfunction (NLUTD) is a major problem in patients with various neurological disorders, and may result in debilitating symptoms and serious complications, including chronic renal failure and recurrent urinary tract infections. Clinically, stroke is associated with voiding dysfunction. However, lower urinary tract function evaluation in an intracerebral hemorrhage (ICH) model has not, to the best of our knowledge, been reported. Therefore, in the present study, lower urinary tract function in ICH-induced rats was investigated and the results were compared with those obtained in normal rats. The effects of ICH on peripheral bladder function and central micturition centers [medial preoptic area, ventrolateral gray, pontaine micturition center and spinal cord (lumbar 4 (L4)-L5)] were also examined. Adult female Sprague-Dawley rats were divided into two groups: Control ICH-induced. Induction of ICH in the hippocampal CA1 region was performed using a stereotaxic frame and type IV collagenase. The effects of ICH on the central micturition centers were investigated by simultaneously determining the extent of neuronal activation (c-Fos) and nerve growth factor (NGF) expression, and assessing voiding function (urodynamically using cystometry). The results revealed that induction of ICH significantly enhanced bladder contraction pressure and time, while simultaneously reducing voiding pressure and time. Furthermore, the c-Fos and NGF expression levels in the neuronal voiding centers were significantly increased in the rats with induced ICH as compared with the control rats. Therefore, this ICH-induced NLUTD rat model may be a more appropriate method to analyze NLUTD in stroke patients than a cerebral infarction model, as the former more accurately reflects the nature of the hemorrhage in the two types of stroke.

The objective of this study was to report bladder dysfunction and cystometric findings in a systematically studied cohort of Huntington's disease (HD) patients. In HD patients and asymptomatic HD gene carriers a urinary function questionnaire, neurologic assessment using the Unified Huntington's Disease Rating Scale, and postvoid residual volume measurement were applied. All patients were also invited to cystometric studies. Urinary function data were compared to control men and women. The most common symptoms in 54 HD patients (24 men) were those of bladder overactivity (men/women 54%/40%), followed by urinary incontinence (29%/43%) and symptoms of disturbed bladder emptying (25%/40%). Using urinary function questionnaires severe bladder dysfunction was found in 4%/0%, moderate in 21%/23%, and mild in 25%/30% of HD men/women. Urinary symptoms interfered with daily life in 21%/37% and sexual life in 21%/33% of sexually active HD men/women. In 5 HD men and 1 woman, increased postvoid residual volume (>100 ml) was found. Compared to 49/55 control men/women urinary incontinence, and urgency were more common in HD men, but not in HD women (urinary incontinence reported 10%/38% of control men/women). Cystometry, performed in 12 HD patients and 1 of 10 asymptomatic HD gene carriers, demonstrated detrusor-sphincter dyssynergia in 5 (42%), detrusor overactivity in 2 (17%), and reduced detrusor capacity in 2 (17%) HD patients. Our study demonstrated significant urinary symptoms in HD patients, which reduced their quality of life. Physicians helping HD patients should also consider this largely neglected aspect of the disease.

Purpose: To investigate the prevalence of lower urinary tract symptoms (LUTS) and urinary incontinence (UI) in elementary school aged children in Manisa., Materials and Methods: Dysfunctional Voiding and Incontinence Scoring System (DVIS) which was developed in Turkey is used. A total of 416 children, 216 (51.9%) male and 200 (48.1%) female were recruited in this study., Results: Mean age of children was 10.35 ± 2.44 years (median10 years). Daytime UI frequency was 6.7% (28 child), nocturnal incontinence 16.6% (69 child) and combined daytime and nocturnal incontinence 4.1% (17 child). There was no statistically significant difference in the prevalence of nocturnal and or daytime UI between male and female gender. Mean DVIS score was 2.65 ± 3.95 and gender did not affect total DVIS points. The mean ages of achieving daytime bowel and bladder control were all significantly correlated with DVIS points. DVIS points were positively correlated with the history of UI of the family. Total points were increased when the father was unemployed., Conclusion: UI negatively influences health related quality of life of the family and child, so it is important that awareness of the UI and symptoms of lower urinary tract dysfunction.

Background: The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood., Objective: To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms., Design, Setting, and Participants: Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20-46 yr of age (n=42 582) from the Swedish Twin Registry., Measurements: Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity., Results and Limitations: A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45-65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates., Conclusions: This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Nocturnal enuresis is a common, genetically heterogeneous disorder. Family, twin and segregation analyses have demonstrated a high heritability. Molecular genetic linkage studies have identified several loci on different chromosomes. Much less is known about the genetics of daytime urinary incontinence. In this study we identify familial patterns in a large, representative sample of children with nocturnal enuresis and daytime urinary incontinence., Materials and Methods: Participants were a cohort of more than 8,000 children enrolled in the population based Avon Longitudinal Study of Parents and Children, a prospective longitudinal study of an original birth cohort of nearly 14,000 children. Parents completed postal questionnaires asking about their own nocturnal enuresis and urinary incontinence. At the age of 7½ years extensive data on nocturnal enuresis and urinary incontinence of their children were obtained., Results: At the age of 7½ years the prevalence of nocturnal enuresis was 15.5%. Infrequent nocturnal enuresis affected 12.8% of children and severe nocturnal enuresis (2 or more episodes weekly) affected 2.6%. The prevalence of urinary incontinence was 7.8%, and 6.8% had infrequent and 1.0% had severe daytime urinary incontinence. Of the 11,650 mothers who provided data on their own nocturnal enuresis and urinary incontinence 8.8% had nocturnal enuresis and 0.7% had daytime urinary incontinence. Of the 7,897 fathers 9.6% had nocturnal enuresis and 0.3% had daytime urinary incontinence. There were significant associations between parental and child nocturnal enuresis, and parental and child urinary incontinence. Specifically the odds ratios for severe child nocturnal enuresis were 3.63 times higher in maternal and 1.85 times higher in paternal nocturnal enuresis. The odds ratios for severe child urinary incontinence were 3.28 times higher in maternal and 10.1 times higher in paternal urinary incontinence. The associations were less pronounced between parental nocturnal enuresis and child urinary incontinence, as well as between parental urinary incontinence and child nocturnal enuresis., Conclusions: Formal genetic risks exist for nocturnal enuresis and urinary incontinence, especially in severe incontinence. The magnitude of effects for child nocturnal enuresis and urinary incontinence is comparable. While the heritability of nocturnal enuresis is well-known, the familiarity of urinary incontinence has been underestimated., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The fields of tissue engineering and regenerative medicine have seen major advances over the span of the past two decades, with biomaterials playing a central role. Although the term "regenerative medicine" has been applied to encompass most fields of medicine, in fact urology has been one of the most progressive. Many urological applications have been investigated over the past decades, with the culmination of these technologies in the introduction of the first laboratory-produced organ to be placed in a human body.1 With the quality of life issues associated with urinary incontinence, there is a strong driver to identify and introduce new technologies and the potential exists for further major advancements from regenerative medicine approaches using biomaterials, cells or a combination of both. A central question is why use biomaterials? The answer rests on the need to make up for inadequate or lack of autologous tissue, to decrease morbidity and to improve long-term efficacy. Thus, the ideal biomaterial needs to meet the following criteria: (1) Provide mechanical and structural support, (2) Maintain compliance and be biocompatible with surrounding tissues, and (3) Be "fit for purpose" by meeting specific application needs ranging from static support to bioactive cell signaling. In essence, this represents a wide range of biomaterials with a spectrum of potential applications, from use as a supportive or bulking implant alone, to implanted biomaterials that promote integration and eventual replacement by infiltrating host cells, or scaffolds pre-seeded with cells prior to implant. In this review we shall discuss the structural versus the integrative uses of biomaterials by referring to two key areas in urology of (1) pelvic organ support for prolapse and stress urinary incontinence, and (2) bladder replacement/augmentation., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Ectopic ureters (EUs) associated with varying combinations of urinary incontinence, hydronephrosis, and urinary tract infection have been identified in related North American Entlebucher Mountain Dogs., Objectives: To characterize the disease phenotype in affected dogs and evaluate possible modes of inheritance., Animals: Twenty client-owned Entlebucher Mountain Dogs. Nine dogs had clinical signs of urinary tract disease., Methods: Prospective case series in which 17 dogs were evaluated with excretory urography, ultrasonography, and urethrocystoscopy. Three additional dogs were evaluated by necropsy alone. Clinical and pedigree histories from 165 North American Entlebuchers were compiled for analysis., Results: Eleven female and 2 male dogs were found to have EUs. Six females and 1 male were continent. Bilateral intravesicular ectopic ureters (IVEUs) were identified in 9 dogs, bilateral extravesicular ectopic ureters (EVEUs) in 3 dogs, and 1 dog had IVEU and EVEU. Hydronephrosis was identified in 5 dogs, 3 of which had bilateral IVEUs. Two necropsied dogs had bilateral hydronephrosis with presumed ureterovesical junction obstruction associated with chronic granulation tissue or lymphoplasmacytic inflammation. Twenty-six dogs with EUs were identified in the pedigree. Because of incomplete penetrance, mode of inheritance could not be determined., Conclusions and Clinical Importance: Ureteral ectopia is common in North American Entlebucher Mountain Dogs and clinical signs alone could not reliably predict disease phenotype. EVEUs were associated with urinary incontinence and occasionally hydronephrosis. IVEUs were clinically silent or associated with hydronephrosis. Further analyses are necessary to confirm and characterize the hereditary nature of the disorder., (Copyright © 2010 by the American College of Veterinary Internal Medicine.)

Background: The bladder's regulatory function is influenced by central serotonergic modulation. T102C polymorphism of the serotonin 2A (5-HT(2A)) receptor gene is associated with urinary incontinence (UI) that has been reported by older community dwellers. We analyzed the association between 5-HT(2A) receptor gene polymorphism and urodynamic tests for UI in older women., Methods: A case-control study was performed with 68 older women submitted to urodynamic evaluation and 162 older women without urinary problems (self-reported), all community dwellers enrolled in the Gravataí-GENESIS Project, Brazil. Clinical interviews, complete urodynamic evaluation following the International Continence Society Report on Good Urodynamic Practice (case group), and molecular analyses were performed (case and control groups). Serotonin 2A receptor gene genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme HpaII. We excluded patients with diabetes mellitus, neurologic damage, and diuretic intake., Results: The subjects' mean (SD) age was 68.1 (6.5) years (range, 60-92 years). We found an association between the TT genotype versus CC + CT genotypes and UI (P = 0.013; odds ratio, 2.69; 95% confidence interval, 1.37-5.29) and, in addition, an association with urgency UI, maximal cystometric capacity (TT, 349 mL; CC + CT, 429.5 mL [P = 0.047]), detrusor pressure at maximum cystometric capacity (TT, 11 cm H(2)O; CC + CT, 6.75 cm H(2)O [P = 0.032]), and detrusor compliance (TT, 34 mL/cm H(2)O; CC + CT, 61.25 mL/cm H(2)O [P = 0.006])., Conclusions: We confirmed our previous findings of a genetic influence of the TT genotype on UI involving the serotonergic pathway among older women. Further investigations including 5-HT(2A) expression in the bladder, pelvic floor, and striated sphincter muscle must be performed.

Predisposition factors for pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress urinary incontinence (SUI), urge urinary incontinence (UUI), and hernias, are not well understood. We assessed linkage evidence for PFDs in mostly sister pairs who received treatment for moderate-to-severe POP. We genotyped 70 affected women of European descent from 32 eligible families with at least two affected cases by using the Illumina 1 million single-nucleotide polymorphism (SNP) marker set. Parametric linkage analysis with general dominant and recessive models was performed by the Markov chain Monte Carlo linkage analysis method, MCLINK, and a set of SNPs was formed, from which those in high linkage disequilibrium were eliminated. Significant genome-wide evidence for linkage was identified on chromosome 9q21 with a HLOD score of 3.41 under a recessive model. Seventeen pedigrees (53%) had at least nominal evidence for linkage on a by-pedigree basis at this region. These results provide evidence for a predisposition gene for PFDs on chromosome 9q.

There is growing interest in causal factors for pelvic floor disorders. These conditions include pelvic organ prolapse and urinary and fecal incontinence and are affected by a myriad of factors that increase occurrence of symptomatic disease. Unraveling the complex causal network of genetic factors, birth-induced injury, connective tissue aging, lifestyle and comorbid factors is challenging. We describe a graphical tool to integrate the factors affecting pelvic floor disorders. It plots pelvic floor function in 3 major life phases: (1) development of functional reserve during an individual's growth, (2) variations in the amount of injury and potential recovery that occur during and after vaginal birth, and (3) deterioration that occurs with advancing age. This graphical tool accounts for changes in different phases to be integrated to form a disease model to help assess the overlap of different causal factors.

The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 +/- 6.35 years (60-100 years), with 16.9% males and 83.1% females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78%, the CT genotype frequency was 55.24% and the TT genotype frequency was 22.98%. We found an independent significant association between the TT genotype (35.7%) and urinary incontinence (OR = 2.06, 95%CI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.

We report the case of an elderly man of Greek background who presented with progressive cognitive decline and motor parkinsonism on a background of a strong family history of Parkinson's disease. Associated symptoms included visual hallucinations, excessive daytime drowsiness, recurrent falls, orthostatic hypotension and urinary incontinence. His major clinical symptoms and signs fulfilled consensus criteria for a clinical diagnosis of dementia with Lewy bodies. An alpha-synuclein gene mutation analysis for the G209A substitution was positive. We conclude that the alpha-synuclein (G209A) gene mutation genotype should be considered in the differential diagnosis of dementia with Lewy bodies, particularly in patients with European ancestry and a family history of Parkinson's disease.

Objectives: FG syndrome is an X-linked recessive mental retardation syndrome with ano-rectal anomalies, constipation, and occasional urinary incontinence. Because tethered spinal cord syndrome (TCS) has similar symptoms, we evaluated imaging for TCS in patients with FG syndrome., Study Design: Patients were recruited from the International FG Syndrome Support Group, and an FG Syndrome Consensus Group reviewed clinical histories, medical records, and photographs of each responding patient. Results of cranial and spinal imaging studies were available for 12 patients., Results: Of 12 boys with FG syndrome, 6 had hypoplasia of the corpus callosum, and 3 of these had TCS (all with constipation and urinary symptoms). The other 9 did not have urinary symptoms. After surgical untethering, bowel and bladder symptoms improved., Conclusions: Tethered spinal cord syndrome occurred in 25% of patients with FG syndrome associated with hypoplasia of the corpus callosum and causing bowel and bladder incontinence. A high index of suspicion is necessary for early diagnosis, and timely intervention results in significant improvement in symptomatology.

Objective: Congenital connective tissue dysfunction may partly be responsible for female pelvic organ prolapse and urinary incontinence. We undertook a heritability study to determine whether mobility of the bladder neck, one of the main determinants of stress urinary incontinence, is genetically influenced., Design: Heritability study using a twin model and structural equation modelling., Setting: Queensland Institute of Medical Research, Brisbane, Australia., Population: One hundred and seventy-eight nulliparous Caucasian female twins and their sisters (46 monozygotic pairs, 24 dizygotic pairs and 38 sisters) aged 18-24 years., Methods: We performed translabial ultrasound, supine and after bladder emptying, for pelvic organ mobility. Urethral rotation and bladder neck descent were calculated using the best of three effective Valsalva manoeuvres., Main Outcome Measures: Bladder and urethral mobility on Valsalva assessed by urethral rotation, vertical and oblique bladder neck descent., Results: Genetic modelling indicated that additive genes accounted for up to 59% of the variance for bladder neck descent. All remaining variance appeared due to environmental influences unique to the individual, including measurement error., Conclusion: A significant genetic contribution to the phenotype of bladder neck mobility appears likely.

The majority of research on urinary incontinence (UI) has been conducted with Caucasian populations. This correlational, descriptive study was designed to identify prevalence and risk factors for Ul and to determine the types of incontinence most commonly seen in healthy African-American women. Results of this study showed that age and education were risk factors for Ul in African-American women. It is suggested that African-American women be routinely screened for symptoms of Ul as a part of preventive health care.

Objective: To determine whether there is an increased risk of urinary incontinence in daughters and sisters of incontinent women., Design: Population based cross sectional study., Setting: EPINCONT (the epidemiology of incontinence in the county of Nord-Trøndelag study), a substudy of HUNT 2 (the Norwegian Nord-Trøndelag health survey 2), 1995-7., Participants: 6021 mothers, 7629 daughters, 332 granddaughters, and 2104 older sisters of 2426 sisters., Main Outcome Measures: Adjusted relative risks for urinary incontinence., Results: The daughters of mothers with urinary incontinence had an increased risk for urinary incontinence (1.3, 95% confidence interval 1.2 to 1.4; absolute risk 23.3%), stress incontinence (1.5, 1.3 to 1.8; 14.6%), mixed incontinence (1.6, 1.2 to 2.0; 8.3%), and urge incontinence (1.8, 0.8 to 3.9; 2.6%). If mothers had severe symptoms then their daughters were likely to have such symptoms (1.9, 1.3 to 3.0; 4.0%). The younger sisters of female siblings with urinary incontinence, stress incontinence, or mixed incontinence had increased relative risks of, respectively, 1.6 (1.3 to 1.9; absolute risk 29.6%), 1.8 (1.3 to 2.3; 18.3%), and 1.7 (1.1 to 2.8; 10.8%)., Conclusion: Women are more likely to develop urinary incontinence if their mother or older sisters are incontinent.

BK large conductance voltage- and calcium-activated potassium channels respond to elevations in intracellular calcium and membrane potential depolarization, braking excitability of smooth muscle. BK channels are thought to have a particularly prominent role in urinary bladder smooth muscle function and therefore are candidate targets for overactive bladder therapy. To address the role of the BK channel in urinary bladder function, the gene mSlo1 for the pore-forming subunit of the BK channel was deleted. Slo(-/-) mice were viable but exhibited moderate ataxia. Urinary bladder smooth muscle cells of Slo(-/-) mice lacked calcium- and voltage-activated BK currents, whereas local calcium transients ("calcium sparks") and voltage-dependent potassium currents were unaffected. In the absence of BK channels, urinary bladder spontaneous and nerve-evoked contractions were greatly enhanced. Consistent with increased urinary bladder contractility caused by the absence of BK currents, Slo(-/-) mice demonstrate a marked elevation in urination frequency. These results reveal a central role for BK channels in urinary bladder function and indicate that BK channel dysfunction leads to overactive bladder and urinary incontinence.

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5-14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage ( P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04-6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.

Introduction: Antimuscarinic drugs have frequently been used for the treatment for patients with an overactive bladder (OAB) and there have been many studies on the distribution of muscarinic receptor subtypes in the bladder. However, the distribution of muscarinic receptor subtypes in OAB patients has not been well investigated. In this study we investigated the distribution of muscarinic receptor subtypes with mRNA and protein expressions in patients with and without OAB, and investigated both the dome and trigone area., Methods: Samples of bladder smooth muscle were obtained from 10 individuals, five patients with OAB and a non-OAB group consisting of five patients who received radical cystectomy., Results: The M2 receptor was predominant, but there was no significant difference in the level of M2 expression between the groups in the dome area. M5 expression in the dome area was significantly higher in the OAB group than in the non-OAB group. In the trigone area, the level of M2 mRNA expression was the highest in the non-OAB group, and was significantly lower in the OAB group. The levels of M1 and M5 mRNA expression were also observed in samples obtained from the trigone area., Conclusion: The multiformity of the muscarinic receptor subtypes in human bladder smooth muscle was confirmed, and our results suggest that the efficacy of a given pharmacologic therapy differs from patient to patient.

The Epidemiologic Issues in Urinary Incontinence: Current Databases and Future Collaborations Symposium included an international group of 29 investigators from 10 countries. The purpose of the symposium was to discuss the current understanding and knowledge gaps of prevalence, incidence, associated risk factors, and treatment outcomes for incontinence in women. During the symposium, investigators identified existing large databases and ongoing studies that provide substantive information on specific incontinence research questions. The investigators were able to form an international collaborative research working group and identify potential collaborative projects to further research on the epidemiology of urinary incontinence and bladder dysfunction.

Urinary incontinence is a significant health care problem affecting women and men of all races and cultures. Existing literature provides a limited evidence base with which to influence UI practice. More research is needed to fully understand the influences of gender, race, culture, or ethnicity on the patient's experience of UI and its management. The matter is particularly relevant for nurses who want to understand and help people cope with the adverse physical and psychosocial consequences of this chronic, socially isolating, and potentially devastating disorder.

Objective: The purpose of this study was to evaluate whether urinary incontinence is more common in family members of women with incontinence compared with continent individuals., Study Design: Women who were examined at 2 different outpatient facilities over a 2-year period received a questionnaire that covered social, behavioral, and medical issues. They were also asked whether they had a family member who complained of urinary incontinence and, if so, the degree of the relationship. Subjects were excluded for the following reasons: not mentally competent, difficulty understanding the written English language, and a history of bladder cancer or of acquired or congenital neuropathy. Statistical analyses were conducted with chi-squared tests for differences between groups; a probability of <.05 was defined as significant., Results: A total of 833 women received the questionnaire; 667 women answered the question about urinary incontinence in family members. These 667 women were divided into 3 groups: group I, 441 incontinent women from the first facility; group II, 112 continent women from the first facility; and group III, 114 continent women from the second facility. Women with at least 1 relative with urinary incontinence were 34.9% in group I, 16.1% in group II, and 5.3% in group III. This difference was statistically significant. In a comparison of group I and group II, the odds that an incontinent woman had at least 1 relative with incontinence were 2.6 times higher (95% CI, 1.50-4.48); comparing group I and group III, the odds were 9.6 times higher (95% CI, 4.17-22.25)., Conclusion: In our study population, women with urinary incontinence were more likely to have at least 1 family member also with incontinence when compared with women who were continent.

Purpose: We studied a large 4-generation family in which night and day voiding problems segregated in an autosomal dominant pattern with a high penetrance. We mapped the gene(s) causing these forms of incontinence using a total genome scan approach., Materials and Methods: The family comprises 74 subjects in 4 generations. The clinical phenotypes were evaluated by detailed questionnaires and frequency volume charts. Genetically, a genome scan approach with 500 polymorphic marker systems was used to localize a chromosome area for the trait(s) and to narrow down a candidate region. The 3 different genetic models studied were 1) a single gene causing either day, night or day and night incontinence; 2) a gene primarily causing night incontinence; and 3) 2 different genes each causing only day or night incontinence., Results: For model 2 we found 2 areas that gave a high lod score on 2-point analysis (D4S2960, 4p16.1, Z = 3.66 and D12S86, 12q24.2, Z = 3.22) on chromosome 4p and 12q. With an estimated penetrance of 75% only 4p linkage was significant. Models 1 and 3 were excluded as causes due to lack of the affected haplotype in affected subjects. Based on manual haplotype and 2-point analyses, all other areas were excluded for linkage., Conclusions: The most likely genetic model in this kindred seems to be a gene located on chromosome 4p16.1 causing primarily nocturnal enuresis. However, involvement of chromosome 12q24.3 cannot be excluded for linkage. The dopamine receptors DRD5 and D1B are mapped to chromosome 4p16. These genes are candidate genes for nocturnal enuresis and urge incontinence.

Purpose: Formal studies of the genetics of enuresis have been performed since the 1930s and molecular genetics since 1995, both highlighting the importance of hereditary factors in the etiology of nocturnal enuresis. We summarize the current state of knowledge with respect to the genetics of nocturnal enuresis and its genotype-phenotype interactions., Materials and Methods: A comprehensive review of the published data available on the genetic basis of enuresis was performed., Results: Genetic factors are the most important in the etiology of nocturnal enuresis but somatic and psychosocial environmental factors have a major modulatory effect. Most commonly, nocturnal enuresis is inherited via an autosomal dominant mode of transmission with high penetrance (90%). However, a third of all cases are sporadic, and the difference between sporadic and familial forms is not known. Four gene loci associated with nocturnal enuresis have been identified but the existence of others is presumed (locus heterogeneity). All likely candidate genes have been excluded so far. There is no specific association among the different loci, type of wetting and other aspects of the phenotype. All subtypes of nocturnal enuresis (primary, secondary, combined day/night wetting) are susceptible to comparable genetic influences. Certain syndromes of day wetting follow their own genetic mechanisms but this association with the genetics of nocturnal enuresis is not known., Conclusions: Nocturnal enuresis is a common, genetic and heterogeneous disorder. The associations between genotype and phenotype are complex and are susceptible to environmental influences. Therefore, exact assessment of the clinical phenotype and identification of intermediary phenotypes or traits are needed. Future research will focus on the identification of genes, gene products and their interaction with environmental factors.

Previous studies demonstrated that acute irritation of the lower urinary tract (LUT) induces the expression of the immediate early gene, c-fos, in lumbo-sacral spinal cord neurons "J. Neurosci. 12 (1992) 4878" "Am. J. Physiol. 265 (1993) 326" "Somatosens. Mot. Res. 15 (1998) 5". This effect was mediated in part by activation of capsaicin-sensitive bladder afferents "Am. J. Physiol. 265 (1993) 326". Here we investigate the role of preprotachykinin gene products (neurokinin A and substance P) in the response to bladder irritation in urethane-anesthetized mice. Acute irritation of the LUT (intravesical acetic acid) induced smaller numbers of Fos-positive neurons in the spinal cord of mice with a mutated preprotachykinin gene than in wild type mice. Increased Fos expression following LUT irritation or a sham operation in wild type mice was also significantly reduced by pretreatment with the NK2 antagonist, MEN 11420, but Fos expression in mutant mice was not altered by the antagonist. During cystometrograms, a significantly higher percentage (83%) of mutant mice exhibited urinary retention and overflow incontinence as compared to wild type controls. These findings suggest an involvement of tachykinins and NK2 receptors in the response to chemical irritation of the LUT in mice and also suggest that tachykinins contribute to the regulation of normal reflex bladder activity.

Clozapine is an effective atypical antipsychotic that has high affinity for many neurotransmitter receptors. Among the adverse effects of clozapine, urinary incontinence is commonly found and is suggested to be caused by alpha-adrenergic blockade. We tested the hypothesis that clozapine-induced urinary incontinence is related to a genetic variant of the alpha(1a)-adrenoceptor. We also tested whether the alpha(1a)-receptor gene confers susceptibility to schizophrenic disorders. Our result indicated that the alpha(1a)-adrenoceptor gene polymorphism investigated plays no major role in the pathogenesis of schizophrenia or in clozapine-induced urinary incontinence. Considering the superior effects of clozapine and its potent adrenergic antagonistic effects, it is of interest to investigate the association between this polymorphism and the treatment response., (Copyright 2000 S. Karger AG, Basel.)

A machine learning system named Galactica has been developed which uses a genetic algorithm to discover the rules for an expert system from databases. Galactica devised accurate diagnostic rules for female urinary incontinence from difficult heterogeneous data. The percentages of correctly classified stress, mixed and sensory urge incontinence testing cases were 89, 86 and 87%, respectively. However, these rules were rather general, consisting of 4-6 out of 13 conditions available in the data. Diagnostic rules for stress and mixed incontinence extracted from straightforward homogeneous data were highly accurate, classifying 100% of testing cases correctly as well as being specific, having from 10 to 11 conditions. More specific, but less accurate, rules were found from heterogeneous data with a biased fitness function. All of the rules were correct, i.e. every condition in the rules had the expected value specified by the expert. Although, Galactica achieved a slightly better classification than the discriminant analysis, it is argued that the genetic approach is better than the statistical one, due to symbolic rules being comprehensible, whereas understanding a complex mathematical model requires statistical expertise.

Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.