Thomas S.K. Chang

Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME). DESIGN Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS One hundred twenty-six patients with DME. METHODS Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ. MAIN OUTCOME MEASURES The mean change from baseline in best-corrected visual acuity (BCVA) at month 24. RESULTS After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively. CONCLUSIONS Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Immunohistochemical Localization of Nitric Oxide Synthase in the Autonomic Innervation of the Human Penis

An improved understanding of the physiology of penile erection has resulted from recent evidence that implicates nitric oxide as the principal mediator of erectile function. Previously, the neuroanatomy of erection in man was established with descriptions of the autonomic innervation of the pelvic organs and external genitalia. The basis upon which novel physiological concepts of erection relate to earlier neuroanatomical principles remains to be determined. In the present study these relationships were explored with nitric oxide synthase immunohistochemistry and reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry of select pelvic tissue specimens obtained from 4 men (3 at radical prostatectomy and 1 at autopsy). Nitric oxide synthase, the enzyme that catalyzes nitric oxide production, was identified in discrete neuronal locations, including the pelvic plexus, cavernous nerves and their terminal endings within the corporeal erectile tissue, branches of the dorsal penile nerves and nerve plexuses in the adventitia of the deep cavernous arteries. This distribution of nitric oxide synthase-containing nerves suggests that nitric oxide neuronally modulates local vascular smooth musculature of the penis. On this basis, nitric oxide is identified as a neuronal mediator of penile erection in man.

IN VITRO FERTILIZATION IS ASSOCIATED WITH AN INCREASED RISK OF HYPOSPADIAS

PURPOSE The purpose of this study was to determine if there is an increased incidence of hypospadias in male offspring conceived by in vitro fertilization (IVF). MATERIALS AND METHODS A retrospective institutional chart review from 1988 to 1992 and data from the Maryland Birth Defects Registry were statistically analyzed to assess the risk of hypospadias with IVF. RESULTS The data for the 5-year period indicated a 5-fold increased risk of hypospadias after IVF, with an incidence of approximately 1.5% in the IVF group and 0.3% in the control group. The only recognized difference between the groups was maternal progesterone administration in the IVF group but the cause of the increased risk of hypospadias was unknown. The distribution of hypospadias severity was similar in both groups. CONCLUSIONS Male newborns conceived by IVF have a 5-fold increased risk of hypospadias, which may be related to maternal progesterone administration, or other maternal or fetal endocrine abnormalities that may or may not be related to infertility. Health care providers should be aware of this risk so that they can properly counsel infertile couples seeking assisted reproduction by IVF technology.

Antibiotics: potential hazards to male fertility

Individual agents within each of the major classes of antibiotics have been shown to have significant adverse effects on spermatogenesis or spermatozoal function in mammals. For humans, infertility or significant alterations in semen parameters have been well documented for the nitrofurans and for patients on sulfasalazine. Other commonly used antibiotics, such as minocycline, have been shown to be toxic to sperm at any concentration. Until further information is available, clinicians must keep in mind that treatment with antibiotics may adversely affect the fertility potential of men. It is possible that some classes of antibiotic agents, such as the penicillins or the quinolones, may have minimal effects on male fertility and maintain the clinical efficacy for patients requiring long-term antibiotic suppressive therapy. Further investigation is needed into the relative toxicity of antibiotics and the mechanisms by which antibiotics affect spermatogenesis and spermatozoal function. A background of the current state of knowledge regarding the adverse effects of antibiotics on male fertility is presented in this review.

Characterization and localization of nitric oxide synthase in the human prostate

OBJECTIVES To characterize nitric oxide synthase (NOS), which catalyzes nitric oxide (NO) production, in the human prostate using biochemical and immunohistochemical techniques. METHODS NOS catalytic assay and NOS immunohistochemistry were performed on histologically verified nonmalignant prostate tissue obtained from the peripheral and transition zones of seven radical prostatectomy specimens. RESULTS Biochemical analysis revealed NOS activity in the human prostate, with a greater amount in the peripheral zone than in the transition zone (P < 0.01). In both prostate zones, NOS was immunohistochemically localized to nerve fibers and ganglia coursing throughout the smooth musculature of the stroma and to subepithelial nerve plexuses. NOS immunoreactivity was also localized to glandular epithelium. CONCLUSIONS The presence, activity, and distribution of NOS were described in two regions of the human prostate. The present evidence implicates NO in the automatic innervation and physiology of the human prostate. It is proposed that NO may modulate smooth muscle tone and secretory functions in the human prostate, although functional studies are needed to support these hypotheses.

Ablation of the Inferior Mesenteric Plexus in the Rat: Alteration of Sperm Storage in the Epididymis and Vas Deferens

The involvement of the sympathetic nervous system in the transport and storage of spermatozoa in the male reproductive tract was examined by surgically ablating the inferior mesenteric plexus (IMP). One to eight weeks after ablation of the IMP, epididymal weight and the total number of spermatozoa present in the cauda epididymidis were significantly greater in IMP-ablated rats than in sham-operated rats. By contrast, the number of spermatozoa present in the initial segment of the vas deferens was significantly greater than in sham operated controls one week after IMP ablation but returned to control levels at two, four, six and eight weeks. Throughout the experiment, no differences were observed between IMP-ablated and control rats in the percentage of motile cauda epididymal spermatozoa, testicular weight, testicular sperm number or serum testosterone. These data demonstrate that the sympathetic nervous system differentially regulates sperm transport and storage in the male reproductive tract and suggest that the IMP may influence the epididymal maturation of spermatozoa.

Localization of Nitric Oxide Synthase in Spinal Nuclei Innervating Pelvic Ganglia

We employed retrograde axonal tracing techniques and nitric oxide synthase (NOS) and choline acetyltransferase (ChAT) immunohistochemistry to identify NOS-containing neuronal populations within the lumbosacral spinal cord and determine whether these project to the major pelvic ganglion in the adult male Sprague-Dawley rat. Immunohistochemical localizations of NOS included neurons situated at the L5 to S2 segments of the spinal cord, which corresponded to the sacral parasympathetic nucleus. Another prominent locus for NOS was a group of neurons identified in the L1 segment corresponding to the dorsal commissural nucleus. These regions correlated directly with preganglionic parasympathetic and sympathetic neuronal origins, respectively, which were established with ChAT colocalizations. Retrograde tracing verified the projection of these neurons to the pelvis. Additional neuronal localizations of NOS were observed throughout the intermediolateral cell column, involving the superficial laminae of the dorsal horn, in the region surrounding the central canal and occasionally in the medial area of the ventral horn. These results indicate that the regulation of pelvic visceral activity may involve NO-based neuronal mechanisms operating at the level of the lumbosarcal spinal cord.

Relationship between antisperm antibodies and testicular histologic changes in humans after vasectomy

OBJECTIVE To determine whether or not there is an association between testicular histologic changes and antisperm antibodies in vasectomized men. METHODS Morphometry was performed on testicular biopsy specimens obtained from 19 vasectomized men and 21 fertile control subjects. Antisperm antibody status was determined on the serum of each patient and control subject using the indirect immunobead assay. RESULTS Significant increases in seminiferous tubule wall thickness (p < 0.001), focal interstitial fibrosis (p < 0.001), and percent composition of interstitium (p < 0.01) were observed in vasectomized men as compared with control subjects. Serum antisperm activity was present in 74 percent of the vasectomized men but none in the control subjects (p < 0.001). There was no association between testicular histologic changes and immune status. CONCLUSIONS Vasectomized men exhibit significant testicular histologic changes and increased autoimmune activity as compared with fertile control subjects. These histologic changes are not directly associated with antisperm antibody status, suggesting that some other pathophysiologic process must be responsible.

Nitric oxide modulates human chorionic gonadotropin-induced ovulation in the rabbit

OBJECTIVE To examine the potential role of the L-arginine:nitric oxide pathway in hCG-induced ovulation in the rabbit. DESIGN Randomized, controlled animal study. SETTING University research laboratory. INTERVENTION(S) Nitric oxide synthase, the enzyme that produces nitric oxide (NO), was immunohistochemically localized in the ovary. NG-nitro-L-arginine methyl ester (L-NAME), an analogue of L-arginine, which inhibits the enzyme NO synthase, and the inactive D-enantiomer were administered in vivo and/or in vitro via an isolated, perfused ovary preparation during the periovulatory period. MAIN OUTCOME MEASURE(S) Rate of follicular rupture (ovulatory efficiency). RESULT(S) Immunohistochemical staining for NO synthase was localized specifically to the granulosa cell layer of the follicle and the endothelium and adventitia of ovarian blood vessels. In vivo administration of L-NAME significantly reduced the percentage of large follicles that ovulated in response to hCG (treated 24.6%, control 68.1%). Similarly, exposure of the in vitro-perfused ovary to L-NAME significantly reduced follicular rupture (treated 32.8%, control 64.2%). In contrast, addition of an equimolar concentration of D-NAME to the perfusion medium had no significant effect on the rate of ovulation (treated 83.3%, control 61.3%). CONCLUSION(S) The stereospecific inhibition of follicular rupture by the arginine analogue suggests that NO production by the ovary is an important feature of the normal physiologic processes of the periovulatory period.

Reduction of epididymal sperm motility after ablation of the inferior mesenteric plexus in the rat.

Surgical ablation of the inferior mesenteric plexus in the rat results in an excessive accumulation of sperm within the cauda epididymidis. The present study examined the effect of ablation of the inferior mesenteric plexus on the motility of cauda epididymal spermatozoa. One to 8 weeks after ablation of the inferior mesenteric plexus, sperm curvilinear and straight line swimming velocities were reduced significantly compared with sperm curvilinear and straight line swimming velocities from sham-operated controls. Sperm swimming linearity also changed significantly versus controls after inferior mesenteric plexus ablation. Additional experiments using a vasectomy model suggested that the reductions in sperm curvilinear and straight swimming velocities after inferior mesenteric plexus ablation were not primarily the result of tubal obstruction. These data suggest that the sympathetic nervous system may influence epididymal sperm function.