Christopher J. Cold

Sexually responsive vascular tissue of the vulva

To better understand the genital changes that occur during the female sexual response, using a gross anatomical and histological study of the vascular tissue of the vulva, supplemented with magnetic resonance imaging (MRI).

Wisconsin stillbirth services program: A multifocal approach to stillbirth analysis

Stillbirth accounts for about 26,000 deaths annually in the US. In most previous studies, discrete causes are identified in less than half of all stillbirths. In order to identify causes and non‐causal but potentially contributing abnormalities, we analyzed 416 of the most recent (2004–2010) Wisconsin Stillbirth Service Program (WiSSP) cases from a multifocal approach. In 70% of cases a cause sufficient to independently explain the demise was identified including 40% placental, 21.5% fetal, and 12.7% maternal. Results for stillbirths and second trimester miscarriages did not differ significantly. In 95% of cases at least one cause or non‐causal abnormality was recognizable, and in two‐thirds of cases, more than one cause or non‐causal abnormality was identified. In cases with maternal cause, the placenta was virtually always abnormal. Both placentas (59%) and fetuses (38%) were frequently smaller than expected for gestational age. Previous miscarriage and/or stillbirth were risk factors for second and third trimester losses, with 35% of previous pregnancies ending in fetal demise. Recommendations include complete evaluation of all second and third trimester losses with special attention to placental pathology and thorough investigation for multiple causes or abnormalities whether or not a primary cause is initially recognized. Improved understanding of the causes of late miscarriage and stillbirth may contribute to recognition and management of pregnancies at risk and eventually to prevention of stillbirth.

Cutaneous Corpuscular Receptors of the Human Glans Clitoris: Descriptive Characteristics and Comparison with the Glans Penis

INTRODUCTION The female genital sensory pathways that initiate sexual arousal reflexes begin with cutaneous corpuscular receptors in the glabrous genital skin, including those of the glans clitoris. AIM The aim of this study is to characterize the corpuscular receptors of the glans clitoris. In addition, we compared basic features with the receptors of the glans penis. MAIN OUTCOME MEASURE Number of stained receptors. METHODS Five cadaveric vulvectomy specimens and four cadaveric penile specimens were used. They were serially sectioned and stained with hematoxylin and eosin. Selected blocks were stained with Massons trichrome, and immunohistochemical staining was done with neuronal markers S-100 and neurofilament. RESULTS Using the three stains, we identified an abundance of corpuscular receptors within the glans clitoris, as compared with the surrounding prepuce. These receptors were of varied arrangements, situated in the subepithelial tissues of the glans clitoris. They were indistinguishable from the receptors of the glans penis. The number of receptors per 100× high-powered field ranged from 1 to 14, whereas the receptor density in the glans penis ranged from 1 to 3. A second type of receptor, the Pacinian corpuscle, was identified within the suspensory ligament along the trunks of the dorsal nerve but not within the glans itself. CONCLUSIONS The glans clitoris is densely innervated with cutaneous corpuscular receptors, and these receptors are morphologically similar to the corpuscular receptors of the glans penis. The glans clitoris has greater variability in receptor density compared with the glans penis.

ORIGINAL RESEARCH-ANATOMY/PHYSIOLOGYCutaneous Corpuscular Receptors of the Human Glans Clitoris: Descriptive Characteristics and Comparison with the Glans Penis

INTRODUCTION The female genital sensory pathways that initiate sexual arousal reflexes begin with cutaneous corpuscular receptors in the glabrous genital skin, including those of the glans clitoris. AIM The aim of this study is to characterize the corpuscular receptors of the glans clitoris. In addition, we compared basic features with the receptors of the glans penis. MAIN OUTCOME MEASURE Number of stained receptors. METHODS Five cadaveric vulvectomy specimens and four cadaveric penile specimens were used. They were serially sectioned and stained with hematoxylin and eosin. Selected blocks were stained with Massons trichrome, and immunohistochemical staining was done with neuronal markers S-100 and neurofilament. RESULTS Using the three stains, we identified an abundance of corpuscular receptors within the glans clitoris, as compared with the surrounding prepuce. These receptors were of varied arrangements, situated in the subepithelial tissues of the glans clitoris. They were indistinguishable from the receptors of the glans penis. The number of receptors per 100× high-powered field ranged from 1 to 14, whereas the receptor density in the glans penis ranged from 1 to 3. A second type of receptor, the Pacinian corpuscle, was identified within the suspensory ligament along the trunks of the dorsal nerve but not within the glans itself. CONCLUSIONS The glans clitoris is densely innervated with cutaneous corpuscular receptors, and these receptors are morphologically similar to the corpuscular receptors of the glans penis. The glans clitoris has greater variability in receptor density compared with the glans penis.

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Background Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the aetiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. Methods In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. Results Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (eg, psoriasis, ankylosing spondylitis, type I diabetes and coeliac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with eight diseases not previously assessed by GWAS (eg, lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16 484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic aetiologies. Conclusions These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP–disease associations, and is ideal when characterising cross-phenotype associations, and further emphasise the importance of the MHC region in human health and disease.

Structure and innervation of the labia minora: more than minor skin folds.

Objective: The objective of this study was to examine the histologic features of the labia minora, within the context of the female sexual response. Methods: Eight cadaver vulvectomy specimens were used for this study. All specimens were embedded in paraffin and were serially sectioned. Selected sections were stained with hematoxylin and eosin, elastic Masson trichrome, and S-100 antibody stains. Results: The labia minora are thinly keratinized structures. The primary supporting tissue is collagen, with many vascular and neural elements structures throughout its core and elastin interspersed throughout. Conclusions: The labia minora are specialized, highly vascular folds of tissue with an abundance of neural elements. These features corroborate previous functional and observational data that the labia minora engorge with arousal and have a role in the female sexual response.

Surgical anatomy of the dorsal nerve of the clitoris.

The purpose of this study was to describe the distal pathway of the dorsal nerve of the clitoris (DNC) from gross anatomical and histological studies of cadaver specimens.

Severe Pallister-Hall syndrome with persistent urogenital sinus, renal agenesis, imperforate anus, bilateral hypothalamic hamartomas, and severe skeletal anomalies.

We have read with interest the report of Narumi et al. [2010] regarding female genital defects including vaginal atresia and hydrometrocolpos in females with Pallister–Hall syndrome. We would like to add to this literature our report of an extremely severely affected infant who died neonatally due to pulmonary hypoplasia and was found to have severe Pallister–Hall syndrome including, among other features, common urogenital sinus, bilateral renal agenesis, duplicated uterus, and high imperforate anus. This female infant was born to a 25-year-old G3, P1 following a pregnancy complicated by second trimester bleeding and abnormal ultrasound with oligohydramnios, severe mesomelic shortening of all four limbs, tetralogy of Fallot, and posterior fossa anomalies including an arachnoid cyst, and possible occipital encephalocele. Amniocentesis was attempted, but due to the oligohydramnios, the sample was inadequate and only limited studies were possible. The karyotypewas 46XXandcentromere separationwas absent in a very limited study. Testing for atelosteogenesis (DTDST sequencing and FLNB sequencing) and campomelic dysplasia (SOX9 sequencing) was delayed due to tissue culture failure, but ultimately was performed on cord blood with normal results. Due to progressively worsening oligohydramnios (AFI < 1), pulmonary hypoplasia, and profound intrauterine growth retardation, induction was planned at 33 weeks. The infant was very small for gestational age with a birth weight of 1,133 g, crown rump length of 27.5 cm, and head circumference of 26 cm (all <2%) and lived for less than an hour. Her facial appearance was dysmorphic and somewhat suggestive of an orofaciodigital syndrome with sloping forehead, short downslanting palpebral fissures, narrow nasal bridge with bulbous nasal tip, a pit in the center of the philtrum, cleft palate, virtually absent vermilion of the upper lip, smallmouth, and severemicrognathia (Fig. 1). The neckwas shortwith excess skin, nippleswere lowset, and therewas a mild pectus excavatum.Therewas imperforate anus and a common genitourinary opening with prominent labia majora and absent labia minora. The limbs showed severe acromesomelia with knee hyperextension, and bowing of the shins and forearms. In addition to severe brachydactyly, there was polysyndactyly of the hands and

Wisconsin Stillbirth Service Program: Analysis of large for gestational age cases†‡

Since its inception in 1983, the Wisconsin Stillbirth Service Program (WiSSP) has reviewed over 2,600 referrals. Among 2,451 with fetal weight and gestational age recorded, 186 (7.6%) were large for gestational age (LGA), which is more than expected. We reviewed these cases to identify factors causing or contributing to fetal death as well as increased fetal size. LGA losses tended to occur later in pregnancy than non‐LGA losses. The most common cause of death in LGA fetuses was fetal (43.5%), followed by placental (22.6%), and maternal (11.2%), which contrasts with previous studies involving the same database, but unselected for fetal weight, in which 21.5%, 40.0%, and 12.7% had fetal, placental, and maternal causes, respectively. The most common fetal cause was hydrops (60 cases/32.4%), which was most frequently idiopathic (16/26.6%), followed by cardiac (11/18.3%), Turner syndrome (8/13.3%), and twin–twin transfusions (6/10.0%). Placental causes, most commonly abruption and infarct, were more frequent in diabetic mothers, accounting for 33% versus only 18% in the entire LGA group. In the LGA group overall, 21% of mothers were diabetic, and most stillbirths in diabetic mothers occurred after 28 weeks. Despite large placentas (>95th centile) in 71.8% of the LGA cohort compared to 11% previously reported in the entire database, the most extreme LGA cases had a high fetoplacental ratio. We recommend pathologic evaluation of placentas from all stillbirths, close follow‐up of pregnancies complicated by diabetes, and continued research into causes and pathophysiology of hydrops.

Human Papillomavirus Link to Circumcision Is Misleading

To the Editors: Physical examination is the consensus gold standard for determining circumcision status in men. In their study of Mexican military men, Lajous et al. ([1][1]) found that self-report of circumcision status had a sensitivity of 57.14% and a positive predictive value of 8.33% whenTo the Editors: Physical examination is the consensus gold standard for determining circumcision status in men. In their study of Mexican military men, Lajous et al. (1) found that self-report of circumcision status had a sensitivity of 57.14% and a positive predictive value of 8.33% when compared with physical examination. In other words, of the men who were considered circumcised, only 8.33% of them actually were. If the authors had physical examination data on their subjects, why did they use self-report as measure of circumcision status when they knew it could not be as accurate as the physical examination data? The increase in statistical power using the 95 men who reported themselves as circumcised as opposed to using the 14 men who were actually circumcised is more than offset by using an invalid measure. It would have been helpful if the authors had presented their analysis using the gold standard. As it stands, the authors’ conclusion that circumcision was protective against human papillomavirus (HPV) infection is misleading. The more appropriate conclusion is that the mistaken belief of being circumcised is protective. Can the extremely low positive predictive value of selfreport of circumcision status be a result of lack of familiarity with the term ‘‘circumcision’’ that has been reported in Spanish speakers in the United States (2)? Does this mean that the 88 men who misidentified themselves as circumcised were less educated or less literate than men who correctly identified themselves, or did they have a ‘‘short’’ foreskin as described in South America mestizos (3)? Finally, the authors should be congratulated on obtaining cultures from a broad array of genital sources. One large study of HPV prevalence failed to obtain specimens from the shaft of the penis (4), which has subsequently been found to be the only location to yield evidence of HPV in the majority of circumcised men with the infection (5). The failure to obtain shaft samples renders the results of this highly publicized New England Journal of Medicine study meaningless. Newer studies have found HPV DNA in the seminal vesicles, epididymis, vas deferens, Leydig cells, Sertoli cells, and probably germinal cells (6). Consequently, the validity of any future study of HPV infection in male genitalia will depend on the thoroughness of search for evidence of HPV.