Aging-associated prostate smooth muscle hypercontractility in rats

Abstract Benign prostatic hyperplasia (BPH) is a multifactorial disease, highly associated with aging and characterized by increased prostate smooth muscle (PSM) contractility. Animal models have been employed to explore the aging-associated PSM hypercontractility; however, studies have focused in old animals, neglecting the initial alterations in early ages. The determination of prostatic dysfunctions onset is crucial to understand the BPH pathophysiology and to propose new BPH treatments. Considering that PSM contractility in 10-month-old rats has already been explored, the aim of the present study was to characterize the PSM contractility in younger rats. Male Wistar control (3.5-month-old), 6- and 8-month-old rats were used. Concentration-response curves to phenylephrine and electrical-field stimulation (EFS) were conducted in prostate from all groups. For the first time, we showed that 6- and 8-month-old rats exhibit PSM hypercontractility. The increased prostate contractility to phenylephrine starts around at 6-month-old, worsening during the aging. The 8-month-old rats exhibited hypercontractility to phenylephrine and EFS compared to the control and 6-month-old groups. Reduced phenylephrine potency was observed in 8-month-old rats, indicating an increased age-dependent prostate sensibility to this agonist. Collectively, our findings support the use of 6- and 8-month-old aged rats as new models to explore prostate hypercontractility in BPH.

Prevalence and Clinicopathologic Features of Intestinal Perforation Caused by Segmental Absence of the Intestinal Musculature in Adults.

Segmental absence of the intestinal musculature (SAIM) can cause intestinal perforation in adults. However, its prevalence and clinicopathologic features have not been well-described. This study aimed to determine the prevalence of SAIM-associated perforation and characterize its clinicopathologic features. We retrospectively examined 109 cases of intestinal perforation that underwent surgical resection from January 2009 to December 2019. SAIM was defined as the complete absence of the muscularis propria without extensive inflammation and fibrinous exudation around the perforation. SAIM was the second most frequent cause of perforation (26 cases: 24%), the most frequent cause being related to diverticulitis (39 cases: 36%). The most common site was the sigmoid colon (12 cases: 46.2%). The younger group (aged below 65 y) exhibited more frequent perforation of the upper segments of the gastrointestinal tract (from the duodenum to the descending colon) than the older group (65 y and above) (P=0.0018). No patients developed recurrence. The most common gross features were well-defined circular or small punched-out lesions, and the histologic features were complete absence of the muscularis propria and absence of hemorrhage and necrosis around the area of perforation. The characteristic features of SAIM were unique and their prevalence was higher than previously reported. The precise recognition of SAIM can aid in understanding the cause of perforation and avoiding further unnecessary examinations.

Appendix muscle bands, a forgotten entity.

INTRODUCTION: Appendix muscle bands (AMB) develop from the appendix muscle layer into the mesoappendix. There are few recent publications on this forgotten entity. The objectives of this study were to assess the morphological features of AMB as detected at microscopy examination of appendectomy specimens. METHODS: Sixty-six cases of AMB as detected on appendectomy specimens were assessed for microscopy features on routine hematoxilin and eosin stained tissue slides. The morphological features were analyzed with regard to the main clinico-pathological parameters. RESULTS: AMBs were multiple in 35 cases. Most AMBs were located between the tip and cecal limit, 7 at the tip, and 1 at the cecal limit of the appendectomy specimen. Associated appendix lesions were: acute appendicitis, neuroma, mesoappendix cyst, muscle hiatus, and diverticulae (60,6,2,45, and 1, respectively). In 24 appendices, the AMB developed from the perihiatus muscle. Two microscopy types of AMBs were detected: muscle-AMB and mesoappendix-AMB. CONCLUSION: AMB may be detected incidentally at microscopy of appendectomy specimens. Acute appendicitis was associated in most cases, independently on the microscopy type of AMB. Appendix abnormalities as neuroma, mesoappendix cyst, muscle hiatus, and diverticulae can be associated to AMBs.

A missing distal complex of the external and internal anal sphincters: a macroscopic and histologic study using Japanese and German elderly cadavers.

The lower margin of the internal anal sphincter (IAS) is considered to lie on a J-shaped, subcutaneous part (SCP) of the external anal sphincter (EAS). The lower IAS is united with the J-shaped SCP to form a smooth-striated muscle complex. In the first part of this study, we ensured the presence of the J-shaped EAS in the lateral wall of the anal canal from 12 near-term fetuses. Second, in the lateral anal wall, the examination of the longitudinal section from 20 male and 24 female Japanese cadavers (72-95 years-old) demonstrated that the J-shaped EAS was lost in 15 (34%) due to the very small SCP. Third, we demonstrated that the J-shaped EAS was restricted in the latera anal wall using longitudinal histological sections of the anal canal from 11 male Japanese cadavers (75-89 years-old). Therefore, a site-dependent difference in the IAS-EAS configuration was evident. Finally, we compared a frequency of the lost J-shape between human populations using 10 mm-thick frontal slices from 36 Japanese and 28 German cadavers. The two groups of cadavers were compatible in age (a 0.2-years' difference in males). The macroscopic observations revealed that the J-shaped EAS was absent from 13 (36%) Japanese and six (20%) German specimens, suggesting that the SCP degeneration occurred more frequent in elderly Japanese than elderly German individuals (p < 0.05). The distal IAS-EAS complex seemed to push residual feces out of the anal canal at a transient phase from evacuation to closure. The absence might be the first sigh of anal dysfunction.

Dermoscopic findings of a congenital smooth muscle hamartoma in an infant.

Cutaneous smooth muscle hamartoma is an uncommon, benign tumor developing in the dermis as a result of disorganized hyperproliferation of arrector pili muscle fibers. We present a 1-month-old infant with a congenital smooth muscle hamartoma together with the dermoscopic findings of the case. Dermoscopy can be a helpful non-invasive tool in diagnosing congenital smooth muscle hamartoma due to its distinct findings that help to differentiate it from close mimickers like solitary mastocytoma.

Histopathological and Immunohistochemical Findings in Congenital Pouch Colon: A Prospective Study.

BACKGROUND: There is a paucity of literature on the histopathological aspects of congenital pouch colon (CPC) and immunohistochemical (IHC) assessment has not been reported. So we planned to study the histopathological and IHC findings within the spectrum of CPC and compare the findings with the normal colon. METHODS: This is a descriptive prospective study on CPC patients. There were 49 cases of CPC (42 males and 7 females) and 13 controls. Histological examination was done using hematoxylin and eosin and Masson trichrome stain. IHC analysis was done with actin, myosin, and desmin antibodies, and neuron-specific enolase and S100 markers for counting ganglionic cells. RESULTS: Histologically, congestion, edema and hemorrhage were seen in mucosa, submucosa, and serosa. Muscle layers were disrupted and divided into bands. An additional muscle coat inside of the muscularis propria was seen in CPC types 1 and 2. Mature ganglionic cells were reduced and muscle layers showed reduced and patchy positivity for smooth muscle actin, myosin, and desmin compared to a normal colon. CONCLUSIONS: Histopathological and IHC findings suggest that CPC has distinct defects in the neuromusculature.

Extracorporeal Life Support in Multisystem Smooth Muscle Dysfunction Syndrome.

We describe an infant with congenital mydriasis, patent ductus arteriosus (PDA), pulmonary hypertension, and cystic lung disease. She had all the major components of multisystemic smooth muscle dysfunction syndrome. Due to progressive respiratory deterioration, she required surgical PDA interruption, extracorporeal life support, and subsequent prolonged respiratory support. Genetic testing revealed ACTA2 R179H mutation and cystic lung disease on biopsy.

Segmental Absence of Intestinal Musculature in a 64-Year-Old Female: Case Report and Literature Review.

BACKGROUND Segmental absence of intestinal musculature is a well described entity in premature infants. It presents with peritonitis, bowel perforation, and obstruction. The diagnosis is based on pathologic observation of absence of intestinal musculature. Researchers hypothesized that this entity is a result of a vascular accident during embryogenesis. However, segmental absence of intestinal musculature is no longer limited to the pediatric population. Recently, a few cases have been described in adults with and without significant vascular diseases. This change in the age of the affected population with segmental absence of intestinal musculature makes the understanding of the pathogenesis of this entity even more challenging. CASE REPORT Here, we report a case of segmental absence of intestinal musculature in a 64-year-old female. The patient presented to the emergency room with sudden onset of abdominal pain and signs of peritonitis. Abdominal computed tomography showed free air in the abdomen. Laparotomy was performed, and a perforation involving the descending colon was identified. Left hemicolectomy was performed. Pathologic examination of the resected colon showed segmental absence of intestinal musculature. CONCLUSIONS Although the pathologic diagnosis of segmental absence of intestinal musculature is straightforward, the assumption that this condition is limited to the pediatric population is a major player in overlooking this diagnosis in adults. Pathologists should be aware that this condition can present in adults and is segmental. Gross and microscopic examination of perforated intestine is required to reach the correct diagnosis. To our knowledge, twelve cases of this entity have been described in adults. Here we present the thirteenth case of segmental absence of intestinal musculature in an adult, and we discuss the clinical and pathologic findings of this entity as well as its pathogenesis.

SMAD Signaling Is Required for Structural Integrity of the Female Reproductive Tract and Uterine Function During Early Pregnancy in Mice.

Pregnancy is a complex physiological process tightly controlled by the interplay among hormones, morphogens, transcription factors, and signaling pathways. Although recent studies using genetically engineered mouse models have revealed that ligands and receptors of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) signaling pathways are essential for multiple reproductive events during pregnancy, the functional role of SMAD transcription factors, which serve as the canonical signaling platform for the TGFbeta/BMP pathways, in the oviduct and uterus is undefined. Here, we used a mouse model containing triple conditional deletion of the BMP receptor signaling Smads (Smad1 and Smad5) and Smad4, the central mediator of both TGFbeta and BMP signaling, to investigate the role of the SMADs in reproductive tract structure and function in cells from the Amhr2 lineage. Unlike the respective single- or double-knockouts, female Smad1(flox/flox) Smad5(flox/flox) Smad4(flox/flox) Amhr2(cre/+)conditional knockout (i.e., Smad1/5/4-Amhr2-cre KO) mice are sterile. We discovered that Smad1/5/4-Amhr2-cre KO females have malformed oviducts that subsequently develop oviductal diverticuli. These oviducts showed dysregulation of multiple genes essential for oviduct and smooth muscle development. In addition, uteri from Smad1/5/4-Amhr2-cre KO females exhibit multiple defects in stroma, epithelium, and smooth muscle layers and fail to assemble a closed uterine lumen upon embryo implantation, with defective uterine decidualization that led to pregnancy loss at early to mid-gestation. Taken together, our study uncovers a new role for the SMAD transcription factors in maintaining the structural and functional integrity of oviduct and uterus, required for establishment and maintenance of pregnancy.

Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate.

BACKGROUND: Epithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include αSMA-expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor ß (TGFß) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFß type I receptor tyrosine kinase, ALK5, in epithelial-mesenchymal cross talk during lung morphogenesis. RESULTS: Targeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of αSMA(pos) cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRα, PPARγ, PRRX1, and ZFP423, ALK5-mediated TGFß controls a process that regulates the commitment and differentiation of αSMA(pos) versus lipofibroblast cell populations during lung development. CONCLUSION: ALK5-mediated TGFß signaling controls an early pathway that regulates the commitment and differentiation of αSMA(pos) versus LIF cell lineages during lung development.

Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review.

Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2(nd) to 4(th) middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed.

Fgfr2 is integral for bladder mesenchyme patterning and function.

While urothelial signals, including sonic hedgehog (Shh), drive bladder mesenchyme differentiation, it is unclear which pathways within the mesenchyme are critical for its development. Studies have shown that fibroblast growth factor receptor (Fgfr)2 is necessary for kidney and ureter mesenchymal development. The objective of the present study was to determine the role of Fgfr2 in the bladder mesenchyme. We used Tbx18cre mice to delete Fgfr2 in the bladder mesenchyme (Fgfr2(BM-/-)). We performed three-dimensional reconstructions, quantitative real-time PCR, in situ hybridization, immunolabeling, ELISAs, immunoblot analysis, void stain on paper, ex vivo bladder sheet assays, and in vivo decerebrated cystometry. Compared with control bladders, embryonic day 16.5 (E16.5) Fgfr2(BM-/-) bladders had thin muscle layers with less α-smooth muscle actin and thickened lamina propria with increased collagen type Ia and IIIa that intruded into the muscle. The reciprocal changes in mutant layer thicknesses appeared partly due to a cell fate switch. From postnatal days 1 to 30, Fgfr2(BM-/-) bladders demonstrated progressive muscle loss and increased collagen expression. Postnatal Fgfr2(BM-/-) bladder sheets exhibited decreased agonist-mediated contractility and increased passive stretch tension versus control bladder sheets. Cystometry revealed high baseline and threshold pressures and shortened intercontractile intervals in Fgfr2(BM-/-) versus control bladders. Mechanistically, whereas Shh expression appeared normal, mRNA and protein readouts of hedgehog activity were increased in E16.5 Fgfr2(BM-/-) versus control bladders. Moreover, E16.5 Fgfr2(BM-/-) bladders exhibited higher levels of Cdo and Boc, hedgehog coreceptors that enhance sensitivity to Shh, compared with control bladders. In conclusion, loss of Fgfr2 in the bladder mesenchyme leads to abnormal bladder morphology and decreased compliance and contractility.

Congenital penile pathology is associated with abnormal development of the dartos muscle: a prospective study of primary penile surgery at a tertiary referral center.

PURPOSE: Pathophysiological mechanisms leading to chordee in patients with hypospadias and to the hidden state of buried penis in the prepubic fat remain unclear. Resection of dartos tissue usually makes the penis straight in patients with hypospadias and corrects it in those with buried penis, suggesting a common pathophysiology related to dartos tissue. MATERIALS AND METHODS: Tissue samples from 113 children undergoing primary penile surgery for hypospadias (94 patients), epispadias (1) or buried penis (18) were collected between November 2011 and September 2013. Tissue samples from 79 children undergoing circumcision for nonmedical reasons served as controls. All samples were stained with smooth muscle actin and analyzed by the same pathologist, who was blinded to indication for surgery. Chi-square and Fisher exact tests were applied. RESULTS: Three different dartos tissue patterns were observed. Pattern I (normal) consisted of smooth muscle fibers of dartos tissue organized in a parallel configuration in the subcutaneous tissue. Pattern II was characterized by poorly developed and hypotrophic smooth muscle fibers. Pattern III was determined by randomly distributed smooth muscle fibers in the subcutaneous tissue, without parallel configuration. Pattern I was observed in 45 circumcision specimens (64%). Of buried penis cases 78% were considered abnormal (pattern II in 4 cases and III in 10, p = 0.001). Of hypospadias cases 70% were considered abnormal (pattern II in 31 cases, III in 32, and mixed II and III in 3, p < 0.001). The only epispadias case was designated pattern II. CONCLUSIONS: Congenital penile pathology (hypospadias, buried penis) is associated with structural anomalies in dartos tissue. Further research is needed to unveil the pathophysiology of the condition.

MRI anatomy of anteriorly displaced anus: what obstructs defecation?

BACKGROUND: Anteriorly displaced anus is an anomaly that is debated with regard to its nomenclature, diagnosis and management. OBJECTIVE: To describe MRI anatomy of the anal canal in children with anteriorly displaced anus and its impact on the process of defecation. MATERIALS AND METHODS: We prospectively examined ten children (7 girls, 3 boys; age range 7 months to 8 years, mean 3 years) with anteriorly displaced anus between August 2009 and April 2012. Noncontrast MRI examinations were performed on a 1.5-T magnet. T1- and T2-weighted turbo spin-echo images were acquired in axial, sagittal and coronal planes of the pelvis. The anorectal angle and the relative hiatal distance were measured in mid-sagittal images, and compared with those of a control group using the Mann-Whitney test. RESULTS: In children with anteriorly displaced anus, no anatomical abnormality was depicted at the level of the proximal anal canal. However, the distal anal canal was displaced anteriorly, running out its external muscle cuff, which remained un-displaced at the usual site of the anus. This changes the orientation of the central axis of the anal canal by passing across instead of along the fibers of the longitudinal muscle coat. Children with anteriorly displaced anus had a more obtuse anorectal angle (mean 112.1°), which was significantly greater than that of the control group (mean 86.2°). CONCLUSION: MRI is a valuable tool in studying the anatomy of the anal canal in children with anteriorly displaced anus. The abnormal orientation of the longitudinal muscle across the anal canal can explain the obstructed defecation in these children. Based on this study, it might be of interest to use MRI in studying equivocal cases and children with unexplained constipation.