Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

Purpose: Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A.

Wnt signalling in testicular descent: a candidate mechanism for cryptorchidism in Robinow syndrome.

Background/aims: Robinow syndrome is caused by mutations in Wnt-5a or its receptor Ror2 and can lead to cryptorchidism, though the mechanisms are unclear. Wnt-5a knock-out mice fail to undergo gubernacular swelling, similar to insulin-like hormone 3 (INSl-3) knock-out mice. We aimed to characterise Wnt-5a and Ror2 expression in rat gubernacula to better understand how Wnt-5a signalling affects testicular descent.

Regression of the mammary branch of the genitofemoral nerve may be necessary for testicular descent in rats.

Purpose: Inguinoscrotal testicular descent has been proposed to occur via sensory fibers of the sexually dimorphic genitofemoral nerve, which release a neurotransmitter, calcitonin gene related peptide, to guide the migrating gubernaculum into the scrotum. We hypothesize that androgen mediated regression of the genitofemoral nerve mammary branch is necessary for inguinoscrotal descent in rats. We compared the spatiotemporal development of the genitofemoral nerve in control and antiandrogen treated rats.

Gone with the Wnt: the canonical Wnt signaling axis is present and androgen dependent in the rodent gubernaculum.

Background/aims: How androgens control inguinoscrotal descent remains controversial but may include canonical Wnt signaling via the transcriptional co-activator β-catenin. The canonical Wnt pathway transcribes genes regulating mesenchymal cell migration, fate, extracellular matrix remodeling, and in addition Axin2, a feedback product that reliably identifies Wnt activation. The relationship between β-catenin and androgen receptor warranted investigation into the involvement of the canonical Wnt pathway in testicular descent.

The effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent.

Background/purpose: Inguinoscrotal testicular descent is controlled by androgens between embryonic days E16-19, but androgen receptor (AR) and estrogen receptor (ER) locations are unknown. We aimed to find AR, ERα, and ERβ in the gubernaculum and inguinal fat pad (IFP) in normal rats and after flutamide treatment.

Methods: Sprague-Dawley timed-mated rats were injected with flutamide (75 mg/kg body weight/5% ethanol + oil) on E16-19 or vehicle alone.

Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?

Purpose: Cryptorchidism is the most common male congenital abnormality. The rodent gubernaculum steers the testis from abdomen to scrotum postnatally by eversion and migration through the developing inguinal fat pad (IFP). We hypothesize that extracellular matrix remodeling in/around the gubernaculum is necessary for eversion and migration and is permitted by timed IFP maturation and aimed to examine regional development and matrix metalloproteinase (MMP) content.

Gubernacular development in the mouse is similar to the rat and suggests that the processus vaginalis is derived from the urogenital ridge and is different from the parietal peritoneum.

Background: Gubernacular development and testicular descent have been studied most extensively in rat models, but new transgenic mouse models require a deep understanding of normal mouse development so that results can be extrapolated to the human. We aimed to compare gubernacular anatomy during development in the mouse with that of the rat.

Methods: Time-mated mice (C57BL/6) and Sprague-Dawley rats were used to collect male fetuses at embryonic (E) days E13, E14, E15, E17, E18, and E19 and neonates at postnatal (P) days P0 and P2.

The development and anatomy of the gubernaculum in Hoxa11 knockout mice.

Background: The gubernaculum is central to testicular descent, with recent evidence suggesting that it elongates to the scrotum like a limb bud. Homeobox (Hox) genes involved in limb bud outgrowth are expressed within the gubernaculum. Mice with homozygous Hoxa11 gene deletions have bilateral cryptorchidism.

The common fetal development of the mammary fat pad and gubernaculum.

Background/aims: Recent work both from our laboratory and in marsupial models of testicular descent suggests a strong connection between the mammary line and gubernacular migration. This study investigated the relationship between the mammary fat pad (MFP) that underlies the mammary line and the developing gubernaculum by fluorescent immunohistochemistry.

Methods: Rats at E17 and E19 were fixed and processed for immunohistochemistry.

Gender differences in reduced substance P (SP) in children with slow-transit constipation.

Purpose: Adult slow-transit constipation (STC) occurs predominantly in females and is associated with low numbers of substance P (SP)-containing nerves in colonic circular muscle.

Aim: To determine if reduced SP nerves is female predominant in paediatric STC.

Methods: Children with STC were identified from records of more than 600 nuclear transit studies (NTS) and intestinal biopsies done for intractable chronic constipation between November 1998 and March 2009.

Pregnancy outcomes after maternal exposure to rituximab.

Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure.

Immunoreactivity for high-affinity choline transporter colocalises with VAChT in human enteric nervous system.

Cholinergic nerves are identified by labelling molecules in the ACh synthesis, release and destruction pathway. Recently, antibodies against another molecule in this pathway have been developed. Choline reuptake at the synapse occurs via the high-affinity choline transporter (CHT1).

Hidden in plain sight: the mammary line in males may be the missing link regulating inguinoscrotal testicular descent.

Background/purpose: Inguinoscrotal testicular descent is controlled by androgens and the genitofemoral nerve, but the trigger for what makes the gubernaculum become a migratory organ like a limb bud remains unknown. Recent observations in the flutamide-treated rat suggested a link with the mammary line. We aimed, therefore, to reassess histologic anatomy in 2 different rodent models of androgen blockade, the testicular feminisation mouse (TFM) and the flutamide-treated rat.

Mullerian-inhibiting substance deficiency in transgenic mice interferes with postnatal germ cell development: clues for understanding infertility in cryptorchidism.

Aim: Mullerian-inhibiting substance (MIS) may have a role in postnatal germ cell development, although this remains unproven. Elucidating the regulatory factors is crucial in finding new treatments for preventing infertility in cryptorchidism. We studied germ cell development in neonatal mice with MIS gene or receptor mutation to determine if germ cell development was affected.

The antiandrogen flutamide perturbs inguinoscrotal testicular descent in the rat and suggests a link with mammary development.

Aim: Inadequate androgen activity is a likely cause of cryptorchidism in humans, affecting inguinoscrotal testicular descent. Flutamide, a nonsteroidal antiandrogen, produces cryptorchidism in rats. We aimed to determine the anatomical and histologic effects of flutamide.

Growth of the rat gubernaculum in vitro and localisation of its growth centre.

Purpose: Recent studies suggest that testicular descent is accomplished by outgrowth of the gubernaculum from the abdominal wall. The tip of the gubernaculum has been proposed as the primary site of growth, similar to an embryonic limb bud. We aimed to determine the maximum site of growth in organ culture.

Calcitonin gene-related peptide stimulates mitosis in the tip of the rat gubernaculum in vitro and provides the chemotactic signals to control gubernacular migration during testicular descent.

Background/aims: We investigated whether calcitonin gene-related peptide (CGRP) released from sensory genitofemoral nerve branches could stimulate rodent gubernacular growth and provide chemotactic signals for directing inguinoscrotal gubernaculum migration in vitro.

Materials And Methods: Neonatal rat gubernacula containing a developing cremaster sac (n = 60) were removed at days 0, 2, 4, 6, 8, and 10 (n = 10 per age; n = 5 per experimental group) and placed in organ culture for 24 hours with or without added CGRP (720 nmol/L). The gubernacula were stained for bromodeoxyuridine (BrdU) immunohistochemistry.

Evidence of a novel aggrecan-degrading activity in cartilage: Studies of mice deficient in both ADAMTS-4 and ADAMTS-5.

Objective: To characterize aggrecan catabolism and the overall phenotype in mice deficient in both ADAMTS-4 and ADAMTS-5 (TS-4/TS-5 Delta-cat) activity.

Methods: Femoral head cartilage from the joints of TS-4/TS-5 Delta-cat mice and wild-type mice were cultured in vitro, and aggrecan catabolism was stimulated with either interleukin-1alpha (IL-1alpha) or retinoic acid. Total aggrecan release was measured, and aggrecanase activity was examined by Western blotting using neoepitope antibodies for detecting cleavage at EGE 373-374 ALG, SELE 1279-1280 GRG, FREEE 1467-1468 GLG, and AQE 1572-1573 AGEG.

The anatomy of the cremaster muscle during inguinoscrotal testicular descent in the rat.

Background: Extrapolation of rat testicular descent studies to humans has been criticized because of anatomical differences of the cremaster muscle. Human cremaster is described as a thin strip rather than a large, complete sac as in rats, which is proposed to be more important in propelling the testis during descent. This study investigated cremaster muscle anatomy and ontogeny in both normal and cryptorchid rat models.

Reduced distribution of pacemaking cells in dilated colon.

Interstitial cells of Cajal (ICC) act as pacemaker in gastrointestinal smooth muscle. In animals, small bowel dilatation produces a reduction in ICC numbers and in pacemaker function. With resolution of dilatation, ICC numbers and pacemaking function are partially restored.

Cell membrane and mitotic markers show that the neonatal rat gubernaculum grows in a similar way to an embryonic limb bud.

Aim/background: How the gubernaculum guides the testis into the scrotum remains controversial, with various proposals from passive inversion to active growth. We aimed to determine if the gubernaculum contains an area of active proliferation, such as a "progress zone" in a growing embryonic limb bud, using a fluorescent cell membrane marker, 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate [DiIC12(3)], to trace cell migration, and 5-bromodeoxyuridine (BUDR) (a thymidine analogue) as a mitotic marker.

Methods: Gubernacula were collected from neonatal male rats (n = 42, day 1-2, Sprague-Dawley) and cultured with calcitonin gene-related peptide (CGRP; 714 nmol/L).

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair.

Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate-2 (CS-2) domain and secondarily at the E(373) downward arrow(374)A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan.

Does chemical sympathectomy alter the ontogeny of gubernacular migration in vivo?

Background: Testicular descent occurs in several stages, but the exact mechanism remains obscure. Sympathetic nerves have been proposed to have a role by a possible action on developing cremaster muscle, following observations of sympathetic dysfunction in cremaster from boys with cryptorchidism. This study aimed to see if chemical sympathectomy affected testicular descent in rats.

A new role for androgen in testicular descent: permitting gubernacular cell proliferation in response to the neuropeptide, calcitonin gene-related peptide.

Background/purpose: Cell proliferation at the gubernacular tip increases in response to exogenous calcitonin gene-related peptide (CGRP) during migration into the scrotum. Calcitonin gene-related peptide is contained in the masculinized sensory branches of the genitofemoral nerve. We tested the independent effects of chemical sensory nerve disruption and prenatal androgen blockade on the in vitro gubernacular proliferative response to CGRP.

The role of hepatocyte growth factor in the humoral regulation of inguinal hernia closure.

Background: Calcitonin gene-related peptide (CGRP) is proposed to indirectly cause inguinal hernia closure via hepatocyte growth factor (HGF). Studies have shown that CGRP and HGF cause processus vaginalis (PV) fusion in vitro. We localized the HGF receptor in the PV and tested whether CGRP was responsible for HGF release.