Incidental Tuberculosis Epididymitis/Epididymo-orchitis: A Retrospective Analysis at a Tertiary Center in Taiwan.

OBJECTIVES: To determine the earliest noticeable manifestation and diagnosis in patients diagnosed with tuberculosis (TB) epididymitis/epididymo-orchitis incidentally and to analyze their responses to surgical and medical treatment. METHODS: Patients who underwent surgery for the preliminary impression of chronic epididymitis/epididymo-orchitis or epididymal/testicular tumor from 2000 to 2019 were included in the study. The clinical presentations, laboratory data, radiological examinations, and operative findings were analyzed retrospectively. The outcomes were assessed by the responses to anti-TB chemotherapy and post treatment radiographic evaluations. RESULTS: All of our 25 patients with a mean age of 60.6 years were diagnosed incidentally with TB epididymitis (48.0%) and TB epididymo-orchitis (52.0%) according to the histopathological findings from their surgeries. The presence of a palpable scrotal mass (76.0%), was the major presentation. Nineteen (76.0%) patients had undergone complete chemotherapy after the surgery and 15 (78.9%) patients showed complete recovery. Four (21.1%) patients had unfavorable outcomes, 3 had TB autonephrectomies and 1 required re-surgery years after complete chemotherapy. Of the 3 (12.0%) patients who did not receive chemotherapy after their surgeries, 1 had a TB relapse in the spine and lung and 1 developed bladder cancer years later. CONCLUSION: Tuberculosis epididymitis/epididymo-orchitis is difficult to diagnose. However, some clinical clues can assist including aged patients, extragenital TB histories, poor responses to antibiotic treatment and scrotal skin lesion. Complete anti-TB chemotherapy is mandatory even after the total removal of TB lesion. Supplemental surgical interventions can be considered when the symptoms are not relieved after chemotherapy. Lifespan follow-up is recommended due to high relapse rate.

Di(2-ethylhexyl)phthalate impairs erythropoiesis via inducing Klotho expression and not via bioenergetic reprogramming.

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulated the function of hematopoietic stem and progenitor cells (HSPCs) to influence erythropoiesis, and to explore the associated mechanisms. In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function, but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interfered with erythroid differentiation, we focused on energy metabolism and Klotho expression. DEHP suppressed erythroid differentiation via upregulating Klotho expression, while it did not via modulating cellular bioenergetics. Therefore, our results provided a novel insight into the pathophysiological link between phthalates and dysregulated erythroid differentiation.

The extracellular signal-regulated kinase 1/2 modulates the intracellular localization of DNA methyltransferase 3A to regulate erythrocytic differentiation.

DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is a heritable epigenetic mark, participating in numerous physiological processes. DNMT3A is of particular relevance to hematopoietic differentiation, because DNMT3A mutations are strongly related to hematopoietic malignancies. Additionally, DNMT3A deficiency has been reported to increase the hematopoietic stem cell pool by limiting their differentiation. Our previous study demonstrated that complete loss of DNMT3A resulted in anemia, while DNMT3A haploinsufficiency caused an elevated population of erythrocytes in the content of oncogenic KRAS. Since erythropoiesis is tightly regulated via the erythropoietin (EPO)-mediated RAS-RAF-MEK-ERK1/2 pathway, the question arises whether DNMT3A cooperates with RAS signaling to modulate erythropoiesis. Human leukemia cell lines were used, with differentiation capabilities towards megakaryocyte and erythroid lineages. Overexpression of DNMT3A was found to enhance erythrocytic differentiation of K562 cells, while DNMT3A knockdown suppressed differentiation. Furthermore, higher DNMT3A expression was detected in late-stage mouse erythroblasts along with the DNMT3A translocation to the nucleus. Further studies demonstrated that both ERK1/2-DNMT3A interaction and serine-255 phosphorylation in DNMT3A led to DNMT3A translocation into the nucleus, and modulated erythrocytic differentiation. Our results not only explore the critical role of DNMT3A in erythropoiesis, but also provide a new insight into ERK1/2-DNMT3A interaction in the hematopoietic system.

Male median raphe cysts: serial retrospective analysis and histopathological classification.

BACKGROUND: To review the clinical and pathological characteristics of median raphe cysts and to classify the lesions according to pathogenesis and histopathological findings. METHODS: The medical records of patients who were diagnosed with median raphe cysts between 2001 and 2010 were reviewed to document the clinical presentation and pathological findings of the cysts. RESULTS: Most patients were asymptomatic; however, 9 patients had inflammatory or infectious cysts that were tender or painful. Four patients who had cysts on the parameatus and distal prepuce had difficulty voiding. Hematuria and hematospermia were noted in 2 cases. Thirty-one cysts were lined with an urothelium-like epithelium, and a squamous epithelium lining was found in 3 cases. In 2 cases, a well-formed mucinous glandular structure was observed. The other 20 cysts consisted of mixed epithelia. After excision of the cysts under local or general anesthesia, an urethral fistula developed as a complication in only 1 case. CONCLUSIONS: Median raphe cysts are benign lesions formed due to tissue trapping during the development of urethral folds. The cysts can be defined into 4 types based on pathological findings: urethral, epidermoid, glandular, and mixed. The associated symptoms and signs should be taken into consideration when determining the treatment for the cysts. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http//http://www.diagnosticpathology.diagnomx.eu/vs/7727074877500751.

Temporary vesicostomy-assisted urethroplasty for recurrent obliterated posterior urethral stricture.

BACKGROUND: We report the outcomes of temporary vesicostomy- assisted anastomotic urethroplasty in patients with recurrent obliterated posterior urethral stricture. METHODS: A review of the medical records identified 12 men (mean age 35.8 years) who had undergone anastomotic urethroplasty for recurrent obliterated posterior stricture. Preoperative evaluation of the urethral defect included a simultaneous retrograde urethrogram and cystogram. The mean estimated preoperative radiographic length of the urethral disruption was 4.25 cm. All patients underwent 1-stage bulboprostatic anastomotic repair which was assisted by an intraoperative temporary vesicostomy. RESULTS: The initial objective success rate was 83%. The mean follow-up was 22 months. Voiding cystourethrography performed postoperatively demonstrated a wide, patent anastomosis in all but two cases. Urethroscopy performed 1 month after surgery revealed a patent anastomosis with normal urethral mucosa in all but two patients. The mean peak flow rate at the last follow-up visit was 16.3 ml/s. Two patients developed an anastomotic stricture 6 weeks after surgery that was successfully treated by direct visual internal urethrotomy. Finally, all patients had a patent urethra after salvage treatment postoperatively. CONCLUSION: An open 1-stage temporary vesicostomy- assisted urethroplasty for recurrent obliterated posterior urethral stricture provides satisfactory outcomes and minimal morbidities.

Waist circumference is an independent risk factor for prostatic hyperplasia in Taiwanese males.

PURPOSE: Benign prostatic hyperplasia is a common disease affecting older males. As obesity becomes an increasing problem worldwide, its role in prostatic hypertrophy has been discussed recently. The purpose of this study is to evaluate the relationship between waist circumferences and prostatic hyperplasia in Taiwan. METHODS: There were 539 men enrolled in the study who had health examinations at the Healthcare Center of Chang Gung Memorial Hospital; 53 were excluded because of history of conditions affecting prostatic volume. Their anthropometry was measured and serum prostate-specific antigen (PSA) levels as well as lipid profiles were analyzed. Prostate volume was measured by transrectal ultrasonography performed by experienced urologists. RESULTS: The mean prostate volume was 26.43 mL, whereas mean body mass index (BMI) was 25.27 kg/m(2) and mean waist circumference (WC) was 90.81 cm. By age-adjusted logistic regression, PSA > 4 ng/mL, WC ≥ 90 cm, and BMI > 24 kg/m(2) are associated with increased risk of developing prostatic hyperplasia; only WC ≥ 90 cm can be validated by multiple logistic regression. Further analysis of obesity patterns showed that abdominal overweight/obesity places patients at increased risk independently rather than high WC or high BMI alone. CONCLUSIONS: Study results showed that waist circumference ≥ 90 cm is an independent risk factor of prostatic hyperplasia in Taiwan. Men with abdominal overweight/obesity (WC ≥ 90 cm and BMI > 24 kg/m(2)) have a twofold risk of developing prostatic hyperplasia.

A simplified preputial covering technique to correct buried penis.

OBJECTIVE: We report on refinements of a technique for preputial covering to prevent complications of redundant prepuce, possibly caused by inadequate surgery for buried penis. PATIENTS AND METHODS: From July 2006 to July 2008, 20 consecutive patients (mean age 4.3 years) underwent surgery for buried penis. The surgical techniques consisted of complete unfurling of the penile shaft, fixation of the penile base skin to Buck's fascia and 1 pedicle flap for skin coverage. Our method for preputial covering is novel in that we create a unique 1-flap covering for the ventral skin defect. Patients were monitored postoperatively at 2 weeks, 1 month and 3 months. RESULTS: All patients had good or excellent outcomes, with fewer postoperative complications. Two patients developed subcutaneous hematomas that resolved in 2 weeks with conservative treatment. The mean increase in length of penile projection after surgery was 1.7 cm, a statistically significant difference. All patients had good cosmetic results, with increased visualization of the penile shaft. CONCLUSIONS: The preputial covering technique we devised avoided postoperative bulky prepuce caused by residual redundant prepuce. Repeat surgery was also unnecessary for our patients. Furthermore, parents judged the cosmetic results as excellent.

The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g. the liver) and causes devastating neuronal degeneration. Metabolic defects resulting from Htt aggregates in peripheral tissues also contribute to HD pathogenesis. Simultaneous improvement of defects in both the CNS and peripheral tissues is thus the most effective therapeutic strategy and is highly desirable. We earlier showed that an agonist of the A(2A) adenosine receptor (A(2A) receptor), CGS21680 (CGS), attenuates neuronal symptoms of HD. We found herein that the A(2A) receptor also exists in the liver, and that CGS ameliorated the urea cycle deficiency by reducing mHtt aggregates in the liver. By suppressing aggregate formation, CGS slowed the hijacking of a crucial transcription factor (HSF1) and two protein chaperons (Hsp27 and Hsp70) into hepatic Htt aggregates. Moreover, the abnormally high levels of high-molecular-mass ubiquitin conjugates in the liver of an HD mouse model (R6/2) were also ameliorated by CGS. The protective effect of CGS against mHtt-induced aggregate formation was reproduced in two cells lines and was prevented by an antagonist of the A(2A) receptor and a protein kinase A (PKA) inhibitor. Most importantly, the mHtt-induced suppression of proteasome activity was also normalized by CGS through PKA. Our findings reveal a novel therapeutic pathway of A(2A) receptors in HD and further strengthen the concept that the A(2A) receptor can be a drug target in treating HD.

Human polynucleotide phosphorylase: location matters.

Human polynucleotide phosphorylase (hPNPase) is an RNA-processing enzyme induced in response to type I interferons and during terminal differentiation and cellular senescence. hPNPase was thought to contribute to cellular senescence through its RNA-degrading activity in the cytosol; however, recent studies show that hPNPase localizes to the mitochondrial intermembrane space (IMS) and has a crucial role in maintaining mitochondrial homeostasis. Initial studies have also linked hPNPase to tumorigenesis and the cellular response to viral infection. Its surprising localization in the IMS, which is thought to be devoid of mRNA transcripts, raises questions about where and how hPNPase elicits its numerous suggested functions. Here, we discuss recent advances in understanding the various roles of hPNPase both within and potentially outside of the mitochondria.

Clinical features of testicular torsion and epididymo-orchitis in infants younger than 3 months.

BACKGROUND/PURPOSE: Testicular torsion (TT) and orchitis/epididymo-orchitis (EO) are confusing and difficult for physicians to diagnose in infants younger than 3 months. The aim of the study was to delineate the etiology and the clinical features of TT and EO in this age group. METHODS: During the period between April 1994 and September 2004, medical charts of infants younger than 3 months with TT and EO were reviewed retrospectively. RESULTS: Sixteen patients were eligible for the study, including 9 with TT and 7 with orchitis/EO. Two infants had postnatal torsion, and the testicles were salvaged by emergent surgery. Eighty-six percent (6/7) of infants with EO/orchitis had either abnormal physical signs (fever or scrotal tenderness) or abnormal laboratory findings (leukocytosis or elevated C-reactive protein level). The sensitivity of color Doppler ultrasound to diagnose TT and EO/orchitis was 88% (7/8) and 100% (6/6), respectively. All infants (6/6) with EO/orchitis who were checked for urinary tract infection and sepsis had positive test results. CONCLUSIONS: Pediatricians should examine the testicles meticulously after a baby is born. Orchitis/EO is highly suspected for patients associated with abnormal physical signs and laboratory findings. Prompt prescription of antibiotics is mandatory to avoid serious sequelae.

The TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity.

TCL1 is an AKT kinase coactivator that, when dysregulated, initiates mature lymphocyte malignancies in humans and transgenic mice. While TCL1 augments AKT pathway signaling, additional TCL1 interacting proteins that may contribute to cellular homeostasis or transformation are lacking. Here, an exoribonuclease, PNPase, was identified in a complex with TCL1. The AKT interaction domain on TCL1 bound either RNase PH repeat domain of PNPase without influencing its RNA degrading activity, which was compatible with predicted docking models for a TCL1-PNPase complex. Our data provide a novel protein interaction for mammalian PNPase that may impact TCL1 mediated transformation.

A new function in translocation for the mitochondrial i-AAA protease Yme1: import of polynucleotide phosphorylase into the intermembrane space.

Polynucleotide phosphorylase (PNPase) is an exoribonuclease and poly(A) polymerase postulated to function in the cytosol and mitochondrial matrix. Prior overexpression studies resulted in PNPase localization to both the cytosol and mitochondria, concurrent with cytosolic RNA degradation and pleiotropic cellular effects, including growth inhibition and apoptosis, that may not reflect a physiologic role for endogenous PNPase. We therefore conducted a mechanistic study of PNPase biogenesis in the mitochondrion. Interestingly, PNPase is localized to the intermembrane space by a novel import pathway. PNPase has a typical N-terminal targeting sequence that is cleaved by the matrix processing peptidase when PNPase engaged the TIM23 translocon at the inner membrane. The i-AAA protease Yme1 mediated translocation of PNPase into the intermembrane space but did not degrade PNPase. In a yeast strain deleted for Yme1 and expressing PNPase, nonimported PNPase accumulated in the cytosol, confirming an in vivo role for Yme1 in PNPase maturation. PNPase localization to the mitochondrial intermembrane space suggests a unique role distinct from its highly conserved function in RNA processing in chloroplasts and bacteria. Furthermore, Yme1 has a new function in protein translocation, indicating that the intermembrane space harbors diverse pathways for protein translocation.

Mammalian polynucleotide phosphorylase is an intermembrane space RNase that maintains mitochondrial homeostasis.

We recently identified polynucleotide phosphorylase (PNPase) as a potential binding partner for the TCL1 oncoprotein. Mammalian PNPase exhibits exoribonuclease and poly(A) polymerase activities, and PNPase overexpression inhibits cell growth, induces apoptosis, and stimulates proinflammatory cytokine production. A physiologic connection for these anticancer effects and overexpression is difficult to reconcile with the presumed mitochondrial matrix localization for endogenous PNPase, prompting this study. Here we show that basal and interferon-beta-induced PNPase was efficiently imported into energized mitochondria with coupled processing of the N-terminal targeting sequence. Once imported, PNPase localized to the intermembrane space (IMS) as a peripheral membrane protein in a multimeric complex. Apoptotic stimuli caused PNPase mobilization following cytochrome c release, which supported an IMS localization and provided a potential route for interactions with cytosolic TCL1. Consistent with its IMS localization, PNPase knockdown with RNA interference did not affect mitochondrial RNA levels. However, PNPase reduction impaired mitochondrial electrochemical membrane potential, decreased respiratory chain activity, and was correlated with altered mitochondrial morphology. This resulted in FoF1-ATP synthase instability, impaired ATP generation, lactate accumulation, and AMP kinase phosphorylation with reduced cell proliferation. Combined, the data demonstrate an unexpected IMS localization and a key role for PNPase in maintaining mitochondrial homeostasis.

Selective cytotoxicity of squamocin on T24 bladder cancer cells at the S-phase via a Bax-, Bad-, and caspase-3-related pathways.

Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. We purified squamocin, a cytotoxic bis-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biologic effects on cancer cells. We showed that squamocin was cytotoxic to all the cancer lines tested. Furthermore, squamocin arrested T24 bladder cancer cells at the G1 phase and caused a selective cytotoxicity on S-phase-enriched T24 cells. It induced the expression of Bax and Bad pro-apoptotic genes, enhanced caspase-3 activity, cleaved the functional protein of PARP and caused cell apoptosis. These results suggest that squamocin is a potentially promising anticancer compound.

Anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) promote HER2/neu processing and presentation by dendritic cells: implications in immunotherapy and vaccination strategies.

HER2/neu, a transmembrane glycoprotein overexpressed in several types of human cancers, is a potential target for active immunotherapy. However, this protein and especially its extracellular domain (ECD(HER2)), is weakly immunogenic and is poorly processed by dendritic cells (DCs). Previously, we showed that anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) fusion proteins can enhance the immunogenicity of ECD(HER2) in mice, and that the non-covalent physical association between each antibody fusion proteins and ECD(HER2) was critical to elicit optimal protective immunity against HER2/neu expressing tumors. We now use the professional antigen-presenting DCs to investigate the effect of the antibody fusion protein binding to ECD(HER2) on its trafficking and presentation. We found that when the extracellular domain of HER2/neu fused to ovalbumin (OVA-ECD(HER2)) is bound by HER2/neu-specific antibody-(IL-2) or antibody-(GM-CSF) fusion proteins, the bound antigen is more efficiently processed by murine bone-marrow-derived dendritic cells (BMDCs) and presented to OVA-specific T-cells than the unbound OVA-ECD(HER2). We also found that ECD(HER2) bound by anti-HER2/neu IgG3-(IL-2) is very efficiently internalized and that the internalized ECD(HER2) is not retained in the early endosomal compartments but traffics to the antigen-processing compartments. These results are consistent with our earlier in vivo studies and suggest that both antibody-(IL-2) and antibody-(GM-CSF) fusion proteins can be used to enhance the immune response to poorly immunogenic antigens including tumor-associated antigens (TAAs).

Ureteral reimplantation for vesicoureteral reflux: comparison of minimally invasive extravesical with transvesical and conventional extravesical techniques.

OBJECTIVES: To analyze and compare the different ureteral reimplantation techniques to clarify the decision making for surgical treatment of vesicoureteral reflux. METHODS: From July 1995 to December 2000, 218 patients underwent antireflux surgery. The first 92 cases (143 ureters) were performed with the transvesical technique of Cohen (group 1), the next 37 cases (49 ureters) with the conventional extravesical technique (group 2), and the last 89 cases (113 ureters) with the new minimally invasive technique (group 3). The surgical time, length of hospital stay, postoperative side effects, frequency of pain control, and voiding cystogram findings to ensure the cessation of reflux for all patients were retrospectively analyzed. RESULTS: The success rates were similar among the different procedures. All patients in group 1 required a suprapubic cystostomy, and three had blood clot retention. Four patients in group 2 had bladder inefficiency. The surgical time ranged from 139 to 181 minutes in group 1, 58 to 94 minutes in group 2, and 40 to 61 minutes in group 3. The length of hospital stay ranged from 2.8 to 5.5 days in groups 1 and 2, and no hospital stay was needed in group 3. The frequency of analgesic administration was significantly less in group 2 compared with group 1; however, no analgesia was required in group 3. CONCLUSIONS: The results from our comparison show that the minimally invasive technique can be used as a simple and highly effective interventional procedure with less morbidity for the patient.

Aberrant expression and possible involvement of the leptin receptor in bladder cancer.

OBJECTIVES: To explore the expression patterns and possible involvement of leptin and its receptor in the pathogenesis of urinary bladder cancer, with a focus on transitional cell carcinoma. METHODS: Using reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemistry techniques, we correlated the expression patterns of leptin and its receptor with the occurrence of transitional cell carcinoma. We also applied transient transfection followed by BrdU labeling and immunofluorescent staining to address the effect of the leptin receptor on bladder cancer cell growth. RESULTS: Although leptin was not detected in the bladder tissue specimens, a decreased expression of the leptin receptor was observed in most cancer tissue specimens we analyzed. Furthermore, the forced expression of the leptin receptor in T24 bladder cancer cells prevented them from entering the S phase. CONCLUSIONS: Our data demonstrated for the first time that the leptin receptor is aberrantly expressed in bladder cancer tissue and is possibly involved in the carcinogenesis of bladder cancer.

Neocarzinostatin-induced Rad51 nuclear focus formation is cell cycle regulated and aberrant in AT cells.

DNA double-stranded breaks are the most detrimental form of DNA damage and, if not repaired properly, may lead to an accumulation of chromosomal aberrations and eventually tumorigenesis. Proteins of the Rad51/Rad52 epitasis group are crucial for the recombinational repair of DNA double-stranded breaks, whereas the Rad50/NBS1/Mre11 nuclease complex is involved in both the recombinational and the end-joining repair of DNA double-stranded breaks. Herein, we demonstrate that the chemotherapeutic enediyne antibiotic neocarzinostatin induced Rad51, but not NBS1, nuclear focus formation in a cell- cycle-dependent manner. Furthermore, neocarzinostatin-induced Rad51 foci formation revealed a slower kinetic change in AT cells, but not in wild-type or NBS cells. In summary, our results suggest that neocarzinostatin induces Rad51 focus formation through an ATM- and cell-cycle-dependent, but NBS1-independent, pathway.

Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway.

Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. In this study, we purified annonacin, a cytotoxic mono-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biological effects. Herein, we have shown that annonacin caused significant cell death in various cancer cell lines. T24 bladder cancer cells at the S phase were more vulnerable to the cytotoxicity of annonacin. Furthermore, annonacin activated p21 in a p53-independent manner and arrested T24 cells at the G1 phase. It also induced Bax expression, enhanced caspase-3 activity, and caused apoptotic cell death in T24 cells. In summary, these results suggest that annonacin is potentially a promising anti-cancer compound.

Modeling silica sorption to iron hydroxide.

Experiments were conducted to investigate the fundamentals of silica sorption onto preformed ferric hydroxide at pH 5.0-9.5 and silica concentrations of 0-200 mg/L as SiO2. At all pHs studied, sorption densities exceeding monolayer sorption were observed at silica levels typical of natural waters. Under some circumstances, sorption equaled or exceeded a monolayer while the particle zeta potential remained positive, a phenomenon that is completely inconsistent with available surface complexation models. To address this deficiency, an extended surface complexation model was formulated in which soluble dimeric silica (i.e., Si2O2(OH)5-) sorbs directly to iron surface sites. This new model fit sorption density data up to 0.40 mol SiO2/mol Fe and accurately predicted trends in zeta potential and observed H+ release during silica sorption to ferric hydroxide.