Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis.

Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes of UPEC-infected Irp1-/- mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast with WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testes of Irp1-/- mice upon UPEC infection. Interestingly, in Irp1-/- UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.

Fibrinonecrotic enteritis and orchitis associated with Salmonella enterica subsp houtenae infection in a short-tailed boa (Boa constrictor amarali).

Salmonella enterica subsp houtenae has been recovered from a wide variety of species, including reptiles, and has been linked to important clinical manifestations in snakes and lizards. We describe a case of concomitant fibrinonecrotic enteritis and orchitis associated with S. enterica subsp houtenae infection in a short-tailed boa (Boa constrictor amarali). At necropsy, the mucosa of the large intestine was covered by a focally extensive fibrinonecrotic exudate (diphtheritic pseudomembrane). The left testicle was enlarged, firm and diffusely expanded by a thick fibrinous yellow exudate. Polymerase chain reaction and conclusive antigenic testing indicated that the bacteria isolated from the lesions were S. enterica subsp houtenae, and the virulence genes InvA, slyA, stn and spvC were identified. This report reinforces that, although S. enterica subsp houtenae has been isolated from asymptomatic reptiles, it has the potential to cause life-threatening disease in snakes.

Ultrasound diagnosis of Mondor's disease involving the superficial scrotal veins: Unveiling a rare mimicker of acute scrotal emergencies.

We describe a rare case of Mondor disease of the superficial scrotal veins, which can clinically mimic acute testicular pathologies such as testicular torsion or epididymo-orchitis, and highlight the value of grayscale/Doppler ultrasound examination in distinguishing these entities, which have different management implications.

Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes.

Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD's role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis.

Brucella infection in rough-toothed dolphin (Steno bredanensis) with severe orchitis stranded on the Pacific coast of Japan.

In the western North Pacific, prominent granulomatous testes have been detected in many Brucella-infected common minke whales (Balaenoptera acutorostrata), but there have been no reports in toothed cetaceans. We found severe orchitis with granulomatous lesions in a rough-toothed dolphin (Steno bredanensis) stranded on the Pacific coast of Japan in 2011. Histopathological examination revealed leukocyte infiltration of the lesions. DNA from the lesion was analyzed by PCR and it showed molecular biological similarities with those of Brucella-infected common minke whales and Brucella ceti of sequence-type 27 (ST27). These results suggest that the type of Brucella ceti that infected the dolphin was ST27, which may have caused severe orchitis. This study adds to our understanding of Brucella infections in marine mammals.

Granulomatous orchitis: A case report of misdiagnosis and review of the literature.

Granulomatous orchitis is a relatively rare clinical testicular lesion. The imaging manifestations and clinical symptoms are similar to those of testicular tumors. In order to improve the understanding of this disease, this article reports the ultrasonographic manifestations of a case of granulomatous orchitis and reviews the relevant literature with.

Paediatric acute epididymo-orchitis temporally related to SARS-CoV-2 infection: A case series and review of the literature.

INTRODUCTION: Acute epididymo-orchitis (AEO) is becoming an increasingly common differential diagnosis in children with acute scrotal pain. It has been noted in adult men that SARS-CoV-2 has a propensity for involving the testis and epididymis, affecting sperm and testosterone production. Our literature search revealed only one case report of COVID-19 presenting with epididymo-orchitis in a child. We present three more children who presented with AEO, all recovering from PCR-confirmed SARS-CoV-2 infection. This article reviews the post-inflammatory aetiology of paediatric epididymo-orchitis, and the propensity SARS-CoV-2 has for the testis. PATIENTS AND METHODS: Two pre-pubertal ten-year-old patients presented to the emergency department with a 48-h history of gradual onset unilateral scrotal pain and increasing erythema of the ipsilateral scrotal skin. One fifteen-year-old boy was referred for ongoing symptoms four days following a diagnosis of AEO made by his General Practitioner. On further questioning, all three had PCR-confirmed COVID infection two weeks prior to the onset of their scrotal symptoms and had just ended their isolation period. A literature search was then performed using the keywords SARS-CoV-2, testes and paediatric acute epididymo-orchitis. DISCUSSION: The SARS-Cov-2 virus has a propensity for affecting the testis and epididymis. This puts patients at increased risk of acute epididymo-orchitis during COVID infections. The inflammation induced by the virus appears to affect the cells responsible for testosterone production and sperm quality. However, there is no evidence that viral transmission can happen via semen. CONCLUSION: SARS-Cov-2 infection can lead to acute epididymo-orchitis. Knowledge of this is clinically significant, firstly to avoid unnecessary surgical intervention due to a mistaken diagnosis of testicular torsion and secondly, due to the potential of the virus to affect sperm quality and testosterone production.

Salidroside Ameliorates Furan-Induced Testicular Inflammation in Relation to the Gut-Testis Axis and Intestinal Apoptosis.

Furan is a heat-induced food contaminant, and it causes damage to visceral organs, including the testis. To determine the mechanism of the damage to the testis, a mouse model treated with furan (8 mg/kg bw/day) and salidroside (SAL, 10/20/40 mg/kg bw/day) was established, and levels of testicular functional markers and changes of morphology were investigated in furan-induced mice treated with SAL. The change in related proteins and genes suggested that SAL restored the furan-mediated leaky tight junction and triggered the TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome together with inflammation. To find out the gut-testis axis, microbiota PICRUSt analysis and correlation analysis were conducted to investigate the core microbiota and metabolites. The endoplasmic reticulum stress (ERS)-related key protein levels and the result of transmission electron microscopy suggested that SAL inhibited the furan-induced intestinal ERS. The result of TUNEL and levels of apoptosis-related proteins suggested that furan-induced intestinal apoptosis was alleviated by SAL. Collectively, SAL inhibited furan-induced ERS-mediated intestinal apoptosis through modulation of intestinal flora and metabolites, thus strengthening the gut barrier. It inhibited LPS from entering the circulatory system and suppressed the testicular TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome, which alleviated testicular inflammation.

Testicular involvement of Brucellosis: A 10-year, multicentre study.

INTRODUCTION: The genito-urinary system is one of the most common areas of involvement in brucellosis. To present the epidemiological, clinical, and laboratory characteristics of patients with testicular involvement associated with brucellosis, together with the diagnostic and therapeutic approaches. METHODOLOGY: Patients followed up for brucellosis-related testicular involvement between January 2012 and November 2022 were included in the study. Brucellosis is defined as the production of Brucella spp. in cultures, or clinical symptoms together with the serum standard tube agglutination test titer of ≥ 1/160. Inflammation in scrotal Doppler ultrasonography was based on testicular involvement. RESULTS: A retrospective evaluation was made of the data of 194 patients with brucellosis-related testicular involvement. The rate of determination of testicular involvement in brucellosis was 2.57%. The most affected patients were determined in the 16-30 years age range. On presentation, brucellosis was in the acute stage in 83.7% of patients. The most common symptoms on presentation were swelling and/or pain in the testes (86.6%). In the patients where a spermiogram could be performed, oligospermia was determined in 41.7%, and aspermia in 8.3%. When the testicular involvement of brucellosis was evaluated, epididymo-orchitis was present at the rate of 55.7%, epididymitis at 27.3%, and testis abscess at 5.1%. CONCLUSIONS: Although epididymo-orchitis was the most frequently determined form of involvement in this study, there was also seen to be a significant number of patients presenting with epididymitis. Male patients presented with the clinical status of brucellosis should be questioned about swelling and pain in the testes to avoid overlooking testicular involvement.

Human Tularemia Epididymo-Orchitis Caused by Francisella tularensis Subspecies holartica, Austria.

A previously healthy man in Austria had tularemia epididymo-orchitis develop, leading to unilateral orchiectomy. Francisella tularensis subspecies holartica was detected by 16S rRNA gene sequencing analysis of inflamed granulomatous testicular tissue. Clinicians should suspect F. tularensis as a rare etiologic microorganism in epididymo-orchitis patients with relevant risk factors.

Epidemiology of mumps, mumps complications, and mumps orchitis in Korea using the National Health Insurance Service database.

PURPOSE: To analyze the presentation of mumps and mumps orchitis using the National Health Insurance Service Database (NHISD). MATERIALS AND METHODS: Using information from the NHISD representing all cases of mumps in Korea, data regarding mumps orchitis were analyzed. The International Classification of Diseases, Tenth Revision, and Clinical Modification codes were used for diagnosis. The incidence estimates of the number of mumps cases were analyzed using the Statistical Analysis System (SAS) software. RESULTS: Based on the NHISD, 199,186 people were diagnosed with mumps, and males accounted for 62.3% cases. Teen males accounted for 69,870 cases, the largest number of patients diagnosed with mumps. The annual incidence of mumps increased every year (poisson regression, hazard ratio [HR] 1.026, 95% confidence interval [CI] 1.024-1.027; p<0.025). The risk of mumps was lower in females than that in males (poisson regression, HR 0.594, 95% CI 0.589-0.599; p<0.001). Of the 199,186 patients diagnosed with mumps, 3,872 patients (1.9%) had related complications. Among the mumps complications, the most diagnosed complication was mumps orchitis, which was seen in 41.8% of the males. Mumps orchitis cases accounted for less than 1.5% of the patients with mumps in minors under the age of 20 years and was somewhat higher in 2009 and 2013-2015. CONCLUSIONS: Among the complications related to mumps, meningitis was most common in females, while orchitis was dominant in males. Mumps orchitis also shows periodic outbreaks but is particularly prevalent in adults, which suggests the potential need for additional vaccination against mumps.

Outcome of acute epididymo-orchitis: risk factors for testicular loss.

PURPOSE: Acute epididymo-orchitis (AEO) is a common urological condition characterised by pain and swelling of the epididymis which can affect men of any age. The aetiology and to some extent the management of the patient differ between paediatric and young and older adult groups. METHODS: A retrospective analysis was performed at the University Hospital Limerick from 2012 to 2016. Hospital In-Patient Enquiry (HIPE) data were obtained for all patients diagnosed with orchitis, epididymitis, epididymo-orchitis or testicular abscess over this 5-year period. RESULTS: 140 patients were identified, the age range was 0-89, median age 35.6. These were then split into 3 clinical groups, pre-pubertal (Group 1, 0-15-year-olds), sexually active young men (Group 2a, 16-35-year-olds) and men over 35 (Group 2b). Nine patients had an abscess on ultrasound investigation. There was a significant correlation between the presence of an abscess and the need for an orchidectomy (2 patients, P = 0.035). Two patients were reported as having an atrophic testis following AEO and both were in Group 2b. CONCLUSION: Overall, 7/131 (5%) patients had loss or atrophy of a testicle following an episode of AEO. Nineteen patients had further readmissions with AEO (14%).

NR2C2 of macrophages promotes inflammation via NF-κB in LPS-induced orchitis in mice.

In brief: Bacterial infection can induce testicular inflammation and damage male fertility. This paper reveals the role of nuclear receptor subfamily 2 group C member 2 (NR2C2) in macrophage cells in orchitis caused by bacterial endotoxin lipopolysaccharide (LPS) infection. Abstract: Bacterial infection and induced inflammation are important causes of male infertility. Here, we described the characteristics of expression and the regulatory role of NR2C2 in testicular inflammatory injury induced by infection with the bacterial endotoxin LPS. We found that NR2C2 was highly expressed in the testes and the expression of NR2C2 was upregulated in testicular macrophages in the LPS-induced mouse orchitis model in vivo. In primary testicular macrophages and RAW264.7 cells in vitro, RNA interference with the Nr2c2 gene downregulated the expression of inflammatory factors such as IL-1ß and IL-6. In addition, the knockdown of NR2C2 in macrophages alleviated the inhibitory effect of the inflammatory supernatant secreted by the macrophages on the proliferation of spermatogonia GC-1 SPG cells. Mechanistically, NR2C2 activated NF-κB signaling by binding with DR elements in the promotor of the Nfκb gene and promoted the development of inflammation. These data are the first to confirm that during LPS-induced bacterial infection, NR2C2 plays a proinflammatory role by activating IL-1ß and IL-6 via the NF-κB pathway in macrophages, consequently inhibiting the proliferation of spermatogonia and damaging the quality of sperm. Our findings reveal the important role of NR2C2 in testicular inflammatory injury induced via LPS and provide a new potential target and a molecular basis for the treatment of male infertility caused by bacterial infection.

Acute orchitis deciphered: Coxsackievirus B strains are the main etiology and their presence in semen is associated with acute inflammation and risk of persistent oligozoospermia.

Although various viruses are considered to be the clinical cause for acute orchitis, it is completely unclear to what extent and which viruses are etiologically involved in acute orchitis and what the clinic and course of these patients are like. Therefore, a prospective study was set up to decipher acute isolated orchitis. Between July 2007 and February 2023, a total of 26 patients with isolated orchitis were recruited and compared with 530 patients with acute epididymitis. We were able to show for isolated orchitis, that (1) orchitis is usually of viral origin (20/26, 77%) and enteroviruses with coxsackievirus B strains (16/26, 62%) are predominant, (2) virus isolates could be received from semen indicating the presence of replication-competent virus particles, (3) a polymerase chain reaction (PCR) for enteroviruses should be conducted using semen provided at the onset of disease, because the virus is not detectable in serum/urine, (4) there is a circannual occurrence with the maximum in summer, (5) orchitis is associated with a characteristic inflammatory cytokine panel in the semen and systemic inflammation, (6) orchitis is usually rapidly self-limiting, and (7) about 30% of patients (6/20) suffer ongoing oligozoospermia. These seven emerging aspects are likely to fundamentally change thinking and clinical practice regarding acute isolated orchitis.

Macrophage-Related Testicular Inflammation in Individuals with Idiopathic Non-Obstructive Azoospermia: A Single-Cell Analysis.

Male infertility is a global issue that seriously affects reproductive health. This study aimed to understand the underlying causes of idiopathic non-obstructive azoospermia (iNOA), which is a type of male infertility with unknown origins that accounts for 10-15% of cases. By using single-cell analysis techniques, we aimed to uncover the mechanisms of iNOA and gain insight into the cellular and molecular changes in the testicular environment. In this study, we performed bioinformatics analysis using scRNA-seq and microarray data obtained from the GEO database. The analysis included techniques such as pseudotime analysis, cell-cell communication, and hdWGCNA. Our study showed a significant difference between the iNOA and the normal groups, indicating a disorder in the spermatogenic microenvironment in iNOA. We observed a reduction in the proportion of Sertoli cells and blocked germ cell differentiation. Additionally, we found evidence of testicular inflammation related to macrophages and identified ODF2 and CABYR as potential biomarkers for iNOA.

Functional Imaging of Testicular Torsion.

This article discusses the current clinical role and scope of functional radionuclide imaging using testicular perfusion scintigraphy with 99mTc-pertechnetate in patients presenting with an acute hemiscrotum for an early and reliable diagnosis of testicular torsion. The technique of testicular perfusion scintigraphy is described, and the characteristic findings are detailed with examples. The imaging characteristics of the various phases of testicular torsion and its differentiation from epididymitis and/or epididymo-orchitis and the other related conditions presenting as an acute hemiscrotum are detailed. In some cases, further evaluation by SPECT imaging increases the clarity and accuracy of diagnosis and, on occasion, hybrid SPECT/CT in selected complicated cases improves the diagnostic yield of the perfusion scintigraphy. Ultrasonographic and color Doppler findings are described concurrently with the scintigraphic findings. The several case examples presented demonstrate the additional clinical benefit of complementing functional and structural imaging for improving the sensitivity, specificity and accuracy of testicular imaging in the diagnosis.

Research progress on complications of Brucellosis.

Brucellosis is a common zoonotic disease that is widely spread worldwide and poses a major threat to human health. Clinically, it often presents with non-specific symptoms such as fever, excessive sweating, malaise, myalgia, arthralgia, loss of appetite, weight loss, and enlarged liver, spleen and lymph nodes. The disease has a long and recurrent course, often accumulating in multiple systems and organs. Of these, osteoarticular involvement is the most common complication, with a prevalence of approximately 2-77%, usually manifesting as spondylitis, sacroiliac arthritis and peripheral arthritis. Hepatosplenomegaly is seen in about 50% of patients with brucellosis, and gastrointestinal disturbances such as abdominal pain, nausea, and vomiting are common. Although respiratory involvement is less common, pneumonia, pleurisy, pleural effusion, and pulmonary nodules have been reported. Besides, approximately 2-20% of cases involve infections of the male genitourinary system, mainly manifesting as unilateral epididymal-orchitis and orchitis. The most serious complication facing brucellosis is cardiovascular involvement, and although the overall mortality rate of brucellosis is about 1% and the incidence of brucellosis endocarditis is less than 2%, more than 80% of deaths are associated with endocarditis. Furthermore, brucellosis is complicated by hematologic disease, with anemia occurring in approximately 20-53% of children during the acute phase. In addition, the neurological incidence of brucellosis is about 0.5-25%, mainly manifested as meningitis. In this study, we review the multisystem complications of brucellosis with the aim of improving early diagnosis, timely treatment and prevention of long-term complications.

Insights into Canine Infertility: Apoptosis in Chronic Asymptomatic Orchitis.

Chronic asymptomatic orchitis (CAO) is a common cause of acquired non-obstructive azoospermia in dogs. To understand the impact and mode of action of apoptosis, we investigated TUNEL, Bax, Bcl-2, Fas/Fas ligand, and caspase 3/8/9 in testicular biopsies of CAO-affected dogs and compared the results to undisturbed spermatogenesis in healthy males (CG). TUNEL+ cells were significantly increased in CAO, correlating with the disturbance of spermatogenesis. Bcl-2, Bax (p < 0.01 each), caspase 9 (p < 0.05), Fas, caspase 8 (p < 0.01 each), and caspase 3 (p < 0.05) were significantly increased at the mRNA level, whereas FasL expression was downregulated. Cleaved caspase 3 staining was sporadic in CAO but not in CG. Sertoli cells, some peritubular (CAO/CG) and interstitial immune cells (CAO) stained Bcl-2+, with significantly more immunopositive cells in both compartments in CAO compared to CG. Bcl-2 and CD20 co-expressing B lymphocytes were encountered interstitially and in CAO occasionally also found intratubally, underlining their contribution to the maintenance of CAO. Our results support the crucial role of the intrinsic and extrinsic apoptotic pathways in the pathophysiology of canine CAO. Autoprotective Bcl-2 expression in Sertoli cells and B lymphocytes seems to be functional, however, thereby also maintaining and promoting the disease by immune cell activation.