Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNγR1 (Ifngr1) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.SIGNIFICANCE STATEMENT The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.

Economic Studies Reinforce Efforts to Safeguard Specialty Crops in the United States.

Pathogen-tested foundation plant stocks are the cornerstone of sustainable specialty crop production. They provide the propagative units that are used to produce clean planting materials, which are essential as the first-line management option of diseases caused by graft-transmissible pathogens such as viruses, viroids, bacteria, and phytoplasmas. In the United States, efforts to produce, maintain, and distribute pathogen-tested propagative material of specialty crops are spearheaded by centers of the National Clean Plant Network (NCPN). Agricultural economists collaborated with plant pathologists, extension educators, specialty crop growers, and regulators to investigate the impacts of select diseases caused by graft-transmissible pathogens and to estimate the return on investments in NCPN centers. Economic studies have proven valuable to the NCPN in (i) incentivizing the use of clean planting material derived from pathogen-tested foundation plant stocks; (ii) documenting benefits of clean plant centers, which can outweigh operating costs by 10:1 to 150:1; (iii) aiding the development of disease management solutions that are not only ecologically driven but also profit maximizing; and (iv) disseminating integrated disease management recommendations that resonate with growers. Together, economic studies have reinforced efforts to safeguard specialty crops in the United States through the production and use of clean planting material.

Muscarinic Receptor M3R Signaling Prevents Efficient Remyelination by Human and Mouse Oligodendrocyte Progenitor Cells.

Muscarinic receptor antagonists act as potent inducers of oligodendrocyte differentiation and accelerate remyelination. However, the use of muscarinic antagonists in the clinic is limited by poor understanding of the operant receptor subtype, and questions regarding possible species differences between rodents and humans. Based on high selective expression in human oligodendrocyte progenitor cells (OPCs), we hypothesized that M3R is the functionally relevant receptor. Lentiviral M3R knockdown in human primary CD140a/PDGFαR+ OPCs resulted in enhanced differentiation in vitro and substantially reduced the calcium response following muscarinic agonist treatment. Importantly, following transplantation in hypomyelinating shiverer/rag2 mice, M3R knockdown improved remyelination by human OPCs. Furthermore, conditional M3R ablation in adult NG2-expressing OPCs increased oligodendrocyte differentiation and led to improved spontaneous remyelination in mice. Together, we demonstrate that M3R receptor mediates muscarinic signaling in human OPCs that act to delay differentiation and remyelination, suggesting that M3 receptors are viable targets for human demyelinating disease.SIGNIFICANCE STATEMENT The identification of drug targets aimed at improving remyelination in patients with demyelination disease is a key step in development of effective regenerative therapies to treat diseases, such as multiple sclerosis. Muscarinic receptor antagonists have been identified as effective potentiators of remyelination, but the receptor subtypes that mediate these receptors are unclear. In this study, we show that genetic M3R ablation in both mouse and human cells results in improved remyelination and is mediated by acceleration of oligodendrocyte commitment from oligodendrocyte progenitor cells. Therefore, M3R represents an attractive target for induced remyelination in human disease.

Validity of midday total testosterone levels in older men with erectile dysfunction.

PURPOSE: Based on studies showing the circadian rhythmicity of testosterone the optimal time of day to draw total testosterone in men has classically been reported as between 8 and 11 a.m. However, further studies demonstrated that the testosterone circadian rhythmicity becomes blunted with age. MATERIALS AND METHODS: We retrospectively reviewed the charts of 2,569 men who presented with erectile dysfunction for total testosterone and draw times. We compared the men by age group, including less than 40 years and 5-year groupings after age 40 years. Total testosterone was analyzed for variability during the most common draw time hours (7 a.m. to 2 p.m.). RESULTS: Mean total testosterone at 7 to 9 a.m. and 9 a.m. to 2 p.m. clinically and statistically differed only in men younger than 40 vs 40 to 44 years old (mean difference 207 ng/dl, 95% CI 98-315, p = 0.0004 vs 149 ng/dl, 95% CI 36-262, p = 0.01). No other group showed a clinically and statistically significant difference between those periods. CONCLUSIONS: Total testosterone in men with erectile dysfunction who are younger than 45 years should be drawn as close to 7 a.m. as possible because a statistically and clinically relevant decrease in testosterone will occur during the course of the day. Men older than 45 years with erectile dysfunction can have total testosterone drawn at any time before 2 p.m. without misleading results.

A pilot study to determine penile oxygen saturation before and after vacuum therapy in patients with erectile dysfunction after radical prostatectomy.

INTRODUCTION: Provoked and spontaneous nocturnal erections are thought to play a role in maintenance of male sexual health through oxygenation of the corpus cavernosa. Conversely, hypoxia is thought to be an etiological factor in the pathogenesis of cavernosal fibrosis and long-term erectile dysfunction. It has been hypothesized that the early penile hypoxia after radical prostatectomy (RP) may lead to fibrosis and consequently a decrease in stretched penile length and long-term erectile dysfunction. AIM: The aim of this study was to assess the changes in penile tissue oxygenation with vacuum erection device (VED) use. METHODS: Twenty men between 2 and 24 months following RP were enrolled prospectively. Each man cycled a VED to achieve full erection 10 consecutive times over a period of approximately 2 minutes without constriction ring. MAIN OUTCOME MEASURES: Tissue oximetry was measured at baseline and immediately after VED using a tissue oximeter at five sites: right thigh, right corpora, glans, left corpora, and left thigh. Additional measurements were captured over the course of an hour. RESULTS: Mean age and time from surgery was 58.2 years and 12.6 months, respectively, and the average Sexual Health Inventory for Men score was 7. Use of the VED significantly increased both glanular and corporal oximetry relative to the baseline values for the entire 60 minutes. An initial increase of 55% was seen in corporal oxygenation with VED use. CONCLUSIONS: This is the first study demonstrating that a single, brief application of the VED without a constriction ring results in significant improvement in penile oxygen saturation. The use of a VED has significant benefits for patients both with regard to cost and invasiveness when compared with other penile rehabilitation protocols.

Significance of biofilm for the prosthetic surgeon.

Biofilm formation on implanted medical devices is becoming more recognized as both a common finding and a potential problem. Although seen frequently in nature, these sequestered bacterial communities are proving to be an assiduous enemy as medical device technologies advance. The penile prosthesis has gone through many improvements, now with a more reliable mechanical function and a reduced infection rate. However, there remains a notable increase in infectious risk in revisions compared to novel cases, with many implants found to harbor a subclinical bacterial presence isolated in biofilms. This article focuses on recent updates in implant technology and surgical technique to combat infection, and reviews current research on biofilm prevention and treatment.

Presence of coronary aneurysms during Kawasaki Disease (KD) correlates with lower levels of autoantibodies to both full form and spliced variant of immune regulator Del-1.

Kawasaki disease (KD), a rare multisystem inflammatory condition that predominantly affects children under six years of age, is the leading cause of childhood-acquired heart disease in developed countries. The pathogenesis is unknown, but studies support that an infectious stimulus triggers an autoimmune reaction in a genetically susceptible child. Recent studies demonstrated an association with autoantibody response to Del-1 (also known as EDIL3) in children with KD. Del-1 is an extracellular matrix protein that is expressed both in macrophages and vascular endothelium. Del-1 has an anti-inflammatory role by preventing leucocyte migration to inflammatory sites. Del-1 has two expression variants and genetic variants of Del-1 have been associated with the risk of intracranial aneurysms. Due to the physiologic plausibility for a role during KD, we chose to assess if autoantibodies against DEL-1 are seen in a larger cohort of children with KD and to assess if responses correlated to aneurysm formation. Contrary to prior findings, in comparison to febrile controls, autoantibodies were not overall higher in children with KD. Elevation in Post-IVIG samples in comparison to pre-IVIG and convalescent samples supports the commonality of anti-Del-1 antibodies. Autoantibodies were notably lower in children with KD who had coronary Z score elevations in comparison to those who did not.

Humoral cross-coronavirus responses against the S2 region in children with Kawasaki disease.

Multisystem Inflammatory Syndrome in Children (MIS-C), a post infectious complication of SARS CoV-2 infection, shares enough features with Kawasaki Disease (KD) that some have hypothesized cross-coronavirus (CoV) immunity may explain the shared pathology. Recent studies have shown that humoral cross-reactivity of the CoVs, particularly of OC43, is focused on the S2 region of the Spike protein. Due to efforts utilizing CoV S2 regions to produce a cross-CoV vaccine, we wished to assess SARS-CoV-2 S2 reactivity in children with KD and assess if cardiac involvement in KD correlated with S2 CoV antibody targeting. The presence of cross-reactivity does not distinguish KD from febrile controls and does not correlate with cardiac involvement in KD. These findings support that, in relation to cardiac vascular inflammation, vaccines targeting the S2 region appear to be a safe approach, but there is disparity in the ability of CoV species to raise cross-reactive S2 targeted antibodies.

Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination.

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.

Typical, modified, and atypical measles.

A small outbreak of measles that occurred in August and September of 1975 was studied. One adolescent boy who had received killed measles vaccine 12 years previously had atypical measles, a 31-year-old woman had typical primary measles, and two other boys with measles were live vaccine failures. Of these latter two cases, clinical and serologic findings suggest that one boy had primary vaccine failure and the other may have had a secondary immunologic response. The findings of this study, as well as the results of other recent investigations, suggest that measles will be of increasing concern for the internist.

How is delayed ejaculation defined and treated in North America?

Delayed ejaculation (DE) is an uncommon disorder that is difficult to treat because it is poorly understood. The aim was to evaluate the current opinion and clinical management of DE by practitioners in sexual medicine. Members of the Sexual Medicine Society of North America (SMSNA) were invited by email to participate in a web-based survey. The questionnaire consisted of eight questions pertaining to DE. Questions addressed patient volume, qualification of patient bother, ranking of etiologies, perceived success, treatments used, quantification of symptom resolution, and broad characterization of practitioner type. A total of 94 respondents completed the survey with 73% of those being urologists. Fifty-nine percent of the respondents saw ≤ 2 patients a month with DE and 89% of practitioners felt that DE was moderately or severely bothersome to the patients. Etiology was felt to be from medications and psychological factors primarily. Despite treatment modality, 'seldom' success was obtained for 49% of the time and 'never' for 11%. Carbergoline was the most common selected medication for DE. Academic and private urologists reported 'never' or 'seldom' success with sexual counseling compared to other practitioners, respectively (p = 0.008 and p = 0.001). Respondents who saw ≤ 2 patients per month often reported normalization of hypogonadism 'never' or 'seldom' corrected DE (p = 0.047). Delayed ejaculation is still a poorly understood disorder with inconsistent practice patterns seen among members of the SMSNA. A better understanding of this vexing disorder is needed with efforts placed on research and practitioner education.

Eosinophilia at the time of respiratory syncytial virus bronchiolitis predicts childhood reactive airway disease.

OBJECTIVE: Bronchiolitis in infancy is viewed as a risk factor for childhood asthma, but factors predicting which infants will have persistent wheezing have not been identified. In addition, the nature of the association between the 2 conditions is uncertain. We wished to determine whether eosinophil counts at the time of acute bronchiolitis predicted the presence of wheezing in later childhood. METHODS: We retrospectively identified infants hospitalized with bronchiolitis, determined peripheral blood eosinophil counts at the time of bronchiolitis, and then contacted their families when they had reached 7 years of age. RESULTS: Eosinophil counts at the time of bronchiolitis were greater in subjects who would have wheezing at 7 years of age (median: 98 cells/mm(3)) than in infants who would have no recurrent wheezing (median: 0 cells/mm(3)) or transient wheezing only up to 3 years of age (median: 0 cells/mm(3)). When the effects of family history of asthma, gender, and passive exposure to cigarette smoke were examined, only eosinophilia at the time of bronchiolitis demonstrated a statistically significant relationship to the presence of wheezing at 7 years of age. CONCLUSIONS: Eosinophilia at the time of bronchiolitis generally predicts the development of wheezing persisting into later childhood. Therefore, the association of bronchiolitis and childhood asthma seems more likely to be attributable to an immunologic anomaly that precedes the development of, or is induced by, bronchiolitis rather than to structural damage to the airway as a result of bronchiolitis.

Sepsis syndrome and associated sequelae in patients at high risk for gram-negative sepsis.

We conducted a prospective surveillance study of 80 hospitals across the United States to determine the incidence of sepsis syndrome and its associated sequelae in hospitalized patients over age 18 years who were administered antibiotics for suspected or documented gram-negative infection. A sample of 1754 hospitalized patients were followed from onset of antimicrobial therapy to discharge or death. Mortality rates (MR) varied depending on the suspected source of sepsis syndrome. For patients in whom the syndrome was associated with community-acquired urinary tract infections, mortality was 20% (relative risk [RR] = 0.51, p < 0.05), for those with trauma 20.6% (RR = 0.51, p < 0.05), and patients with nosocomial respiratory tract infections 57.1% (RR = 1.66, p < 0.05). More than two complications occurred in 65.2% of patients under age 60 years (MR 31%), 40.8% of those age 60-80 (MR 42%), and 35.6% of patients older than 80 years (MR 33.3%, p > 0.05). Various patient populations had significant differences in both the incidence of the syndrome and its complications, and consequent mortality. Perhaps morbidity as well as mortality should be used as outcomes when testing the efficacy of innovative therapies for sepsis.

Respiratory syncytial virus immunoglobulin and monoclonal antibodies in the prevention and treatment of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is particularly severe in infants with bronchopulmonary dysplasia (BPD) and in premature infants without BPD. Attempts to develop a vaccine against RSV have been unsuccessful. Passive immunoprophylaxis of premature infants with or without BPD using a hyperimmune human globulin against RSV (RSVIg) decreases the severity of RSV infection such that the rate of hospitalization following infection is reduced by 40%. The severity of illness among hospitalized infants is also reduced. To avoid the difficulties associated with intravenous infusion of immunoglobulins, monoclonal IgG antibodies against the fusion protein of RSV have been developed. In one trial, the antibodies were ineffective, although subsequent trials using higher doses of the antibody show more promising results. Studies of IgA monoclonal antibodies directed against RSV, which are administered in the form of nose drops, are also in progress. None of these preparations appear to be effective in the treatment of established RSV infection. Each of the preparations appeared to be safe, with one exception. Infants with cyanotic heart disease who received RSVIg had an increased risk of surgical complications, perhaps related to increases in serum viscosity as a result of receiving the hyperimmunoglobulin monthly in doses of 750 mg/kg. While definitive cost/benefit analyses are pending, RSVIg may be useful in infants and children with BPD who have current or recent oxygen requirements, as well as in certain premature infants without BPD. Recommendations on the use of RSVIg are provided.

The relationship of RSV-specific immunoglobulin E antibody responses in infancy, recurrent wheezing, and pulmonary function at age 7-8 years.

In order to determine if respiratory syncytial virus (RSV)-specific IgE responses at the time of bronchiolitis in infancy are related to recurrent wheezing and pulmonary function at 7-8 years of age, a cohort of 43 infants was identified at the time of their initial RSV bronchiolitis episode. RSV-specific IgE responses in nasopharyngeal secretions were determined, and patients were then followed prospectively with notation of the number of wheezing episodes and exposure to cigarette smoke at home. At 7-8 years of age the patients underwent skin testing to 7 environmental allergens and pulmonary function testing, including pulse oximetry and methacholine challenge. Pulmonary function following inhalation of bronchodilating agents was compared to baseline pulmonary function results in order to determine if abnormalities of pulmonary function were reversible. Recurrent wheezing following bronchiolitis was associated with the initial RSV-IgE response, as well as with a family history of asthma. Current wheezing at age 7-8 years was associated with 2 or more positive skin tests (P < 0.01), a history of exercise-induced wheezing (P = 0.01), and increased sensitivity to methacholine (P < 0.01). Pulmonary function test results were similar for groups with and without recurrent wheezing following bronchiolitis. For the entire study group, RSV-IgE specific responses were unrelated to pulmonary function, but small airway dysfunction was associated with passive smoking (P < 0.025), and both large airway dysfunction and increased airway reactivity were associated with the number of positive skin tests (P < 0.025). Reduced small airway function improved following bronchodilator inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel pathways in the pathogenesis of respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory infections in infants and children. Extensive research in past decades has expanded our knowledge regarding the specific mechanisms involved in the pathogenesis of RSV bronchiolitis and subsequent chronic obstructive airway disease. Studies of RSV infection are performed in humans, cell culture models, and animal models, each with their own specific limitations. A recently developed murine model in which pulmonary dysfunction can be monitored and quantified appears to add a powerful tool for the study of specific pathogenic mechanisms of experimental RSV infections. Both immunologic and nonimmunologic factors have been implicated in the pathogenesis of RSV-induced diseases. Recently, a hypothesis that RSV bronchiolitis may be the result of production of Th2-type cytokines has become popular. There are, however, studies in human infants with RSV as well as in RSV-infected mice that suggest this theory is incorrect, or at least an oversimplification. There is compelling evidence that cells producing interferon gamma may contribute to RSV-induced wheezing, possibly through induction of leukotriene release. Among the nonimmunologic factors, pulmonary surfactant has recently attracted attention, especially because of the therapeutic implications for infants with severe bronchiolitis. A better understanding of the pathogenesis of RSV-induced diseases will be of considerable help in developing specific therapeutic strategies and in vaccine development.

First Report of Plum pox virus (Sharka Disease) in Prunus persica in the United States.

Plum pox (Sharka) is the most important virus disease of Prunus in Europe and the Mediterranean region and is caused by Plum pox potyvirus (PPV). In September 1999, PPV-like symptoms were observed in peach fruit culls in a packinghouse in Pennsylvania. All symptomatic fruit originated from a single block of peach (P. persica cv. Encore) in Adams County. Trees in the block exhibited ring pattern symptoms on their leaves. A potyvirus was detected in symptomatic fruit using the Poty-Group enzyme-linked immunosorbent assay (ELISA) test from Agdia (Elkhart, IN). Reactions for symptomatic peach fruit and leaves also were positive using triple-antibody sandwich ELISA with the PPV polyclonal antibody from Bioreba (Carrboro, NC) for coating, the Poty-Group monoclonal antibody (MAb; Agdia) as the intermediate antibody, and double-antibody sandwich ELISA with PPV detection kits from Sanofi (Sanofi Diagnostics Pasteur, Marnes-La-Coquette, France) and Agdia and the REAL PPV kit (Durviz, Valencia, Spain) containing universal (5B) and strain typing (4DG5 and AL) PPV MAbs (1). PPV also was identified by immunocapture-reverse transcription-polymerase chain reaction (IC-RT-PCR) amplification and subsequent sequencing of the 220-bp 3' noncoding region (2) (>99% sequence homology to PPV) and by IC-RT-PCR amplification of a 243-bp product in the coat protein (CP) gene (1). The virus was identified as PPV strain D based on serological typing with strainspecific MAbs and on PCR-restriction fragment length polymorphism of the CP IC-RT-PCR product with Rsa1 and Alu1 (1). This is the first report of PPV in North America. References: (1) T. Candresse et al. Phytopathology 88:198, 1998. (2) L. Levy and A. Hadidi. EPPO Bull. 24:595, 1994.

Importance of local immunity in enteric infection.

Evidence suggests that protection against intestinal infections is mediated by an immune system that is unique in many ways. The predominant intestinal immunoglobulin differs in structure, function, and site of origin from those immunoglobulins found in the blood-stream. Cell-mediated intestinal immune responses also may arise separately from those of the rest of the body. Further studies are necessary to characterize the local immune response to many human bacterial, viral, and protozoal pathogens, and to clarify the mechanism of "homing" of immunocompetent cells to the large and small intestine, mammary glands, and other external mucosal surfaces.

Respiratory syncytial virus vaccines: can we improve on nature?

Both inactivated and live RSV candidate vaccines will continue to be tested in infants and young children. Sequential vaccination, with a first dose of live attenuated vaccine followed by boosting with intramuscular subunit vaccines, also is an option. We are encouraged by the fact that influenza subunit and cold-adapted live vaccines are both safe and immunogenic in infants and children of the same age group. Testing of RSV vaccines must proceed at a slower pace because of the phenomenon of vaccine-induced enhanced disease. Curiously, this phenomenon of disease enhancement has not been demonstrated in the case of inactivated influenza or parainfluenza virus vaccines. Another important step in the development of RSV vaccines is to determine a target population. Clearly, children with underlying cardiac or pulmonary disease would benefit from an RSV vaccine. It can be expected that 1% of all infants in the general population will be hospitalized for RSV infection during their first year of life. These infants also would appear to be good candidates for an RSV vaccine, but it is unclear how they would be identified before infection occurs. Immunization of the entire population of infants to protect these 1% would be feasible only if the vaccine were inexpensive and easily administered.

Autoinflation leading to failure of two-piece ambicor implantable penile prosthesis: an outcome from a methodical treatment of recalcitrant stuttering priapism.

Introduction. We present the case of a patient who received a two-piece Ambicor penile prosthesis for idiopathic recurrent "stuttering" priapism refractory to other treatment options. The patient returned unable to deflate the device due to an interesting anatomically induced mechanical failure. Aims. To describe the method and findings of this inflatable prosthesis failure. Results. Prosthesis failure occurred due to restrictive corporal diameter and the unique characteristics of fluid reservoir location in the two-piece inflatable prosthesis. The patient was successfully converted to a semirigid prosthesis with resolution of the pain that was due to his prosthesis autoinflation. Conclusion. Stuttering priapism remains a challenging clinical problem. Penile implantation is a reasonable long-term solution in a patient refractory to less invasive options. In patients with fibrotic corpora, a malleable device should be considered (at least temporarily) if unable to dilate comfortably to 13 mm.