The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

Both initial and deferred PDT combined with IVR to treat polypoidal choroidal vasculopathy show the similar visual and anatomical improvements at 12 months. Initial PDT combination leads to significantly fewer additional treatments.

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The Mullerian ducts are the anlagen of the female reproductive tract, which regress in the male fetus in response to MIS. This process is driven by subluminal mesenchymal cells expressing Misr2, which trigger the regression of the adjacent Mullerian ductal epithelium. In females, these Misr2+ cells are retained, yet their contribution to the development of the uterus remains unknown. Here, we report that subluminal Misr2+ cells persist postnatally in the uterus of rodents, but recede by week 37 of gestation in humans. Using single-cell RNA sequencing, we demonstrate that ectopic postnatal MIS administration inhibits these cells and prevents the formation of endometrial stroma in rodents, suggesting a progenitor function. Exposure to MIS during the first six days of life, by inhibiting specification of the stroma, dysregulates paracrine signals necessary for uterine development, eventually resulting in apoptosis of the Misr2+ cells, uterine hypoplasia, and complete infertility in the adult female.

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Administering intravitreal aflibercept injection for patients with polypoidal choroidal vasculopathy refractory to ranibizumab maintained or improved visual acuity and reduced or eliminated exudative lesions and occluding polypoidal lesions without adverse events with short-term follow-up.

Cerebral blood flow was measured and compared in 10 symmetrical brain regions following unilateral trigeminal ganglionectomy (n = 13), sham operation (n = 6), or trigeminal root section (rhizotomy) (n = 8) in cats. Multiple determinations were obtained in anesthetized and paralyzed animals using radiolabeled mict-ospheres during (i) normocapnia-normotension, (ii) hypercappia (5% C02/95% room air), A third major pathway was recently defined innervating cerebral blood vessels (7). Perivascular sensory axons projecting from the trigeminal ganglia were demonstrated by retrograde (7-9) and orthograde (10) axonal transport techniques as well as by Wallerian degeneration techniques (11) or by surgical lesioning combined with immunohistochemistry (12, 13) or radioimmunoassay (14, 15). Fibers primarily from the ophthalmic division (7, 8) join sympathetic and parasympathetic fibers within the cavernous plexus (11) from which they distribute to the ipsilateral internal carotid artery and the circle of Willis. Trigeminovascular fibers are mainly unmyelinated (16), reside within the adventitial layer, transmit nociceptive information (17, 18), and contain substance P (12), neurokinin A (19), calcitonin gene-related peptide (13), and cholecystokinin 8 (20).In this report, we examined the possibility that sensory axons participate in the regulation of cerebral blood flow based on knowledge that (i) substance P (21, 22), neurokinin A (23), and calcitonin gene-related peptide (13) are cerebrovasodilating molecules; (ii) peptides are released from pial vessels in vitro by depolarizing stimuli (24); and (iii) release mediates vasodilation and/or increases in blood flow following electrical stimulation of sensory nerves in other tissues (25-27). Blood flow was examined during perturbations previously shown to involve nonneurogenic (hypercapnia) and neurogenic mechanisms (at least in part). We conclude that increases in brain blood flow during severe hypertension are not totally passive to the perfusion pressure. Furthermore, increases in flow associated with generalized seizures or hypertension are mediated in part by the trigeminal nerve via local "axon reflex-like" mechanisms involving neuropeptide release from perivascular nerve endings. MATERIALS AND METHODSSham and Lesioning Procedures. Male and female adult mongrel cats (3.0-4.5 kg) were anesthetized with ketamine hydrochloride (30 mg/kg, i.m.) and sodium pentobarbital (10-15 mg/kg, i.p.) and mechanically respirated with halothane anesthesia (0.5-2.0%) as needed. Animals were subjected to unilateral trigeminalectomy as described (15). In this procedure, trigeminal ganglia cell bodies are destroyed and perivascular fibers degenerate accordingly. Shamoperated animals were subjected to craniectomy, exposure of the trigeminal ganglia, as well as an equivalent amount of brain retraction as required for the ganglionectomy.The trigeminal root (that section between the ganglion and the brainstem) was approached by a left suboccipital craniectomy, which extended laterally and ...