Case of persistent corneal epithelial damage after cataract surgery leading to diagnosis of vitamin A deficiency.

PURPOSE: To report our findings of reduced full-field electroretinograms (ff-ERGs) and abnormal optical coherence tomographic (OCT) images in a patient with poor visual acuity after cataract surgery who was eventually diagnosed with vitamin A deficiency (VAD). METHODS: This was a clinical study of a patient who complained of blurred vision after cataract surgery. To determine the cause of the reduced vision, we recorded full-field electroretinograms (ff-ERGs) to determine the scotopic and photopic status of the retina. We also performed optical coherence tomography to assess the changes in the retinal structure. Serological tests were performed. RESULTS: A 74-year-old man presented with persistent corneal epithelial damages and reduced vision that developed after conventional cataract surgery. OCT showed an interrupted ellipsoid zone, and fundus autofluorescence (FAF) showed a severe hypofluorescence in the retina of the left eye. The scotopic ff-ERGs were severely reduced, and the photopic ff-ERGs were mildly reduced. Serological examinations revealed a vitamin A concentration < 7 IU/dL (normal, 97-316 IU/dL). Based on these findings, we diagnosed the patient with VAD and started treatment with oral vitamin A supplements. After three months, his visual acuity, ff-ERGs, and OCT findings recovered to normal levels. The amplitudes and implicit times of the RETeval flicker ERGs increased to be within the normal range, and the hypofluorescence of the left eye disappeared. The length of the photoreceptor outer segments increased after the vitamin A supplementation. CONCLUSION: Our findings indicate that the ERGs are helpful for diagnosing patients with VAD associated with persistent corneal epithelial damages.

Effect of Lipid Composition on the Interaction of Liposomes with THP-1-Derived Macrophages.

Recently, liposomal formulations that target macrophages have been used to treat lung diseases. However, the detailed mechanism of the cellular uptake must be elucidated to identify a formulation with excellent cellular uptake efficiency to treat non-tuberculous mycobacterial lung disease. We studied the effect of lipid composition on the cellular uptake of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (Chol) liposomes with a size of approximately 200 nm into THP-1-derived macrophages. The amount of DPPC/Chol liposomes (80/20 mol%) was greater than that of DPPC/Chol (60/40 mol%) and DPPC/Chol (67/33 mol%) liposomes. The anisotropy of 1,6-diphenyl-1,3,5-hexatriene indicated that the membrane fluidity of the DPPC/Chol (80/20 mol%) liposomes was higher than that of the other two liposomes. DPPC/Chol (80/20 mol%) and DPPC/Chol (67/33 mol%) liposomes were taken up via clathrin- and caveolae-mediated endocytosis and phagocytosis. However, proteins involved in cellular uptake through ligand-receptor interactions were adsorbed to a greater extent on DPPC/Chol (80/20 mol%) liposomes than on DPPC/Chol (67/33 mol%) liposomes. Pretreatment of cells with antibodies against the low-density lipoprotein receptor and scavenger receptor type B1 largely inhibited the uptake efficiency of DPPC/Chol (80/20 mol%) liposomes. Our results indicate that the membrane fluidity of DPPC/Chol liposomes, which is controlled by the Chol ratio, is an important factor in controlling protein adsorption and the subsequent uptake efficiency of liposomes.

Rapid Onset of De Novo Rectal Prolapse Following Colpocleisis.

INTRODUCTION: The aim of this video case series is to demonstrate our experience of the clinical findings and the surgical management of the rapid onset de novo rectal prolapse (RP) following colpocleisis METHODS: This is a case series of three patients who developed de novo RP within 1 month after colpocleisis, which was repaired by laparoscopic ventral mesh rectopexy (LVMR). The video shows the physical, radiological, and intraoperative findings of these patients. A retrospective review of our surgical cases of RP was also performed to analyze the onset timing of de novo RP after various pelvic organ prolapse (POP) procedures. RESULTS: The pathological condition of all three patients' RP was evacuation enterocele, and LVMR was feasible without postoperative complications or recurrences. In the retrospective case review of 158 RP surgeries in our institution (June 2015 to September 2023), 18 cases (11.4%) occurred following POP surgery. De novo RP following colpocleisis developed significantly earlier than those following other procedures (average: 6.1 vs 66.4 months, p = 0.010). CONCLUSIONS: Although de novo RP following colpocleisis is relatively rare, this complication could have a detrimental effect on patients' quality of life. Preoperative informed consent may be advisable before planning colpocleisis.

A 31-year follow-up of those with occult spinal dysraphism, who underwent spinal cord untethering: Lower urinary tract function, skin stigmata, fertility, and work participation.

OBJECTIVES: This study evaluated patients with occult spinal dysraphism who underwent spinal cord untethering. METHODS: Twenty-four patients who visited us between 1983 and 2000 were followed-up for a mean duration of 31 years. We studied their lower urinary tract function, skin stigmata, fertility, and work participation. RESULTS: Questionnaires sent in 2022 revealed that 5 patients had normal voiding (Group A) and 19 patients had abnormal voiding (Group B). Groups A and B underwent spinal cord untethering at a mean age of 5.7 and 13.0 years, respectively, showing a significant statistical difference (p = 0.036). After spinal cord untethering, the number of patients with detrusor normoactivity increased from 0 to 5, i.e., 3 of 6 with detrusor overactivity (50%), 1 of 2 not examined, and 1 of 5 not known. Patients with detrusor underactivity also increased from 11 to 19. Severity of incontinence in the International Consultation on Incontinence Questionnaire-Short Form resulted in a mean value of 2.4 in Group A, which was significantly superior to the mean value of 9.1 in Group B (p = 0.004). Fourteen patients (58.3%) were married and had 21 healthy children. A majority of patients have had full-time jobs. A variety of skin stigmata were present in the lumbosacral region, and changes in vesico-urethral configurations were observed during a video-urodynamic study. CONCLUSIONS: Our study identified that the early timing of spinal cord untethering performed in neonates or infants and detrusor overactivity prior to untethering surgery are important factors in achieving normal bladder function.

An in vitro lipid-mixing assay to investigate the fusion between small extracellular vesicles and endosome.

Small extracellular vesicles (sEVs) such as exosomes can efficiently deliver nucleic acids into the cytosol of recipient cells. However, the molecular mechanism of the subsequent fusion with an endosome is not well understood. In this study, we developed an in vitro lipid-mixing assay using an endosomal-mimicking anionic liposome to investigate the fusion between sEVs and endosomes. We observed that the particle number ratio between the sEVs and the anionic liposomes, the diameter of the liposomes, and the buffer pH were all important for fusion activity. Furthermore, we optimized the liposomal lipid composition and demonstrated that incorporating the anionic lipid bis(monooleoylglycero) phosphate and cholesterol was important for efficient and reliable fusion. Our in vitro assay suggested that a decrease in pH increased the fusion activity. Additionally, it was suggested that this pH-dependent increase in the fusion activity was predominantly due to a change in the sEVs. sEVs possess a larger fusion activity than artificial liposomes that mimic the physicochemical properties of exosomes. These results are consistent with those of previous in vivo studies, supporting the physiological relevance of our system. This study provides an important platform for further research to clarify the molecular mechanisms of fusion between sEVs and endosomes.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Enhancing the Endocytosis of Phosphatidylserine-Containing Liposomes through Tim4 by Modulation of Membrane Fluidity.

Phosphatidylserine (PS) is a unique lipid that is recognized by the endogenetic receptor, T-cell immunoglobulin mucin protein 4 (Tim4), and PS-containing liposomes have potential use in therapeutic applications. We prepared PS-containing liposomes of various lipid compositions and examined how lipid membrane fluidity affects PS recognition by Tim4 and the resulting endocytosis efficiency into Hela cells. Surface plasmon resonance and laurdan studies showed that increasing lipid membrane fluidity increased the stability of the PS-Tim4 interaction but hampered the entry of liposomes into cells. These results show that endocytosis efficiency is determined by balancing opposing forces induced by membrane fluidity. We found that inclusion of the zwitterionic helper lipid, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, into liposomes ensured efficient cellular internalization because the presence of this lipid provides an ideal balance of lipid fluidity and Tim4 affinity. The results showed that PS recognition by Tim4 and the resulting endocytosis efficiency can be maximized by modulating the membrane fluidity of liposomes by selecting a zwitterionic helper lipid. This study improves our understanding of how to rationally optimize nanotechnology for targeted drug delivery.

Characterization of human cystathionine γ-lyase enzyme activities toward d-amino acids.

Various d-amino acids play important physiological roles in mammals, but the pathways of their production remain unknown except for d-serine, which is generated by serine racemase. Previously, we found that Escherichia coli cystathionine ß-lyase possesses amino acid racemase activity in addition to ß-lyase activity. In the present work, we evaluated the enzymatic activities of human cystathionine γ-lyase, which shares a relatively high amino acid sequence identity with cystathionine ß-lyase. The enzyme did not show racemase activity toward various amino acids including alanine and lyase and dehydratase activities were highest toward l-cystathionine and l-homoserine, respectively. The enzyme also showed weak activity toward l-cysteine and l-serine but no activity toward d-amino acids. Intriguingly, the pH and temperature profiles of lyase activity were distinct from those of dehydratase activity. Catalytic efficiency was higher for lyase activity than for dehydratase activity.

Current Status and Challenges of Analytical Methods for Evaluation of Size and Surface Modification of Nanoparticle-Based Drug Formulations.

The present review discusses the current status and difficulties of the analytical methods used to evaluate size and surface modifications of nanoparticle-based pharmaceutical products (NPs) such as liposomal drugs and new SARS-CoV-2 vaccines. We identified the challenges in the development of methods for (1) measurement of a wide range of solid-state NPs, (2) evaluation of the sizes of polydisperse NPs, and (3) measurement of non-spherical NPs. Although a few methods have been established to analyze surface modifications of NPs, the feasibility of their application to NPs is unknown. The present review also examined the trends in standardization required to validate the size and surface measurements of NPs. It was determined that there is a lack of available reference materials and it is difficult to select appropriate ones for modified NP surface characterization. Research and development are in progress on innovative surface-modified NP-based cancer and gene therapies targeting cells, tissues, and organs. Next-generation nanomedicine should compile studies on the practice and standardization of the measurement methods for NPs to design surface modifications and ensure the quality of NPs.

d-Serine and d-Alanine Regulate Adaptive Foraging Behavior in Caenorhabditis elegans via the NMDA Receptor.

d-Serine (d-Ser) is a coagonist for NMDA-type glutamate receptors and is thus important for higher brain function. d-Ser is synthesized by serine racemase and degraded by d-amino acid oxidase. However, the significance of these enzymes and the relevant functions of d-amino acids remain unclear. Here, we show that in the nematode Caenorhabditis elegans, the serine racemase homolog SERR-1 and d-amino acid oxidase DAAO-1 control an adaptive foraging behavior. Similar to many organisms, C. elegans immediately initiates local search for food when transferred to a new environment. With prolonged food deprivation, the worms exhibit a long-range dispersal behavior as the adaptive foraging strategy. We found that serr-1 deletion mutants did not display this behavior, whereas daao-1 deletion mutants immediately engaged in long-range dispersal after food removal. A quantitative analysis of d-amino acids indicated that d-Ser and d-alanine (d-Ala) are both synthesized and suppressed during food deprivation. A behavioral pharmacological analysis showed that the long-range dispersal behavior requires NMDA receptor desensitization. Long-term pretreatment with d-Ala, as well as with an NMDA receptor agonist, expanded the area searched by wild-type worms immediately after food removal, whereas pretreatment with d-Ser did not. We propose that d-Ser and d-Ala are endogenous regulators that cooperatively induce the long-range dispersal behavior in C. elegans through actions on the NMDA receptor.SIGNIFICANCE STATEMENT In mammals, d-serine (d-Ser) functions as an important neuromodulator of the NMDA-type glutamate receptor, which regulates higher brain functions. In Caenorhabditis elegans, previous studies failed to clearly define the physiological significance of d-Ser, d-alanine (d-Ala), and their metabolic enzymes. In this study, we found that these d-amino acids and their associated enzymes are active during food deprivation, leading to an adaptive foraging behavior. We also found that this behavior involved NMDA receptor desensitization.

Glyoxylate reductase/hydroxypyruvate reductase regulates the free d-aspartate level in mammalian cells.

Multiple d-amino acids are present in mammalian cells, and these compounds have distinctive physiological functions. Among the free d-amino acids identified in mammals, d-aspartate plays critical roles in the neuroendocrine and endocrine systems, as well as in the central nervous system. Mammalian cells have the molecular apparatus necessary to take up, degrade, synthesize, and release d-aspartate. In particular, d-aspartate is degraded by d-aspartate oxidase (DDO), a peroxisome-localized enzyme that catalyzes the oxidative deamination of d-aspartate to generate oxaloacetate, hydrogen peroxide, and ammonia. However, little is known about the molecular mechanisms underlying d-aspartate homeostasis in cells. In this study, we established a cell line that overexpresses cytoplasm-localized DDO; this cell line cannot survive in the presence of high concentrations of d-aspartate, presumably because high levels of toxic hydrogen peroxide are produced by metabolism of abundant d-aspartate by DDO in the cytoplasm, where hydrogen peroxide cannot be removed due to the absence of catalase. Next, we transfected these cells with a complementary DNA library derived from the human brain and screened for clones that affected d-aspartate metabolism and improved cell survival, even when the cells were challenged with high concentrations of d-aspartate. The screen identified a clone of glyoxylate reductase/hydroxypyruvate reductase (GRHPR). Moreover, the GRHPR metabolites glyoxylate and hydroxypyruvate inhibited the enzymatic activity of DDO. Furthermore, we evaluated the effects of GRHPR and peroxisome-localized DDO on d- and l-aspartate levels in cultured mammalian cells. Our findings show that GRHPR contributes to the homeostasis of these amino acids in mammalian cells.

Comprehensive analysis of gut microbiota of a healthy population and covariates affecting microbial variation in two large Japanese cohorts.

BACKGROUND: Inter-individual variations in gut microbiota composition are observed even among healthy populations. The gut microbiota may exhibit a unique composition depending on the country of origin and race of individuals. To comprehensively understand the link between healthy gut microbiota and host state, it is beneficial to conduct large-scale cohort studies. The aim of the present study was to elucidate the integrated and non-redundant factors associated with gut microbiota composition within the Japanese population by 16S rRNA sequencing of fecal samples and questionnaire-based covariate analysis. RESULTS: A total of 1596 healthy Japanese individuals participated in this study via two independent cohorts, NIBIOHN cohort (n = 954) and MORINAGA cohort (n = 642). Gut microbiota composition was described and the interaction of these microorganisms with metadata parameters such as anthropometric measurements, bowel habits, medical history, and lifestyle were obtained. Thirteen genera, including Alistipes, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Eubacterium halli group, Faecalibacterium, Fusicatenibacter, Lachnoclostridium, Parabacteroides, Prevotella_9, Roseburia, and Subdoligranulum were predominant among the two cohorts. On the basis of univariate analysis for overall microbiome variation, 18 matching variables exhibited significant association in both cohorts. A stepwise redundancy analysis revealed that there were four common covariates, Bristol Stool Scale (BSS) scores, gender, age, and defecation frequency, displaying non-redundant association with gut microbial variance. CONCLUSIONS: We conducted a comprehensive analysis of gut microbiota in healthy Japanese individuals, based on two independent cohorts, and obtained reliable evidence that questionnaire-based covariates such as frequency of bowel movement and specific dietary habit affects the microbial composition of the gut. To our knowledge, this was the first study to investigate integrated and non-redundant factors associated with gut microbiota among Japanese populations.

Identification and biochemical characterization of threonine dehydratase from the hyperthermophile Thermotoga maritima.

The peptidoglycan of the hyperthermophile Thermotoga maritima contains an unusual component, D-lysine (D-Lys), in addition to the typical D-alanine (D-Ala) and D-glutamate (D-Glu). In a previous study, we identified a Lys racemase that is presumably associated with D-Lys biosynthesis. However, our understanding of D-amino acid metabolism in T. maritima and other bacteria remains limited, although D-amino acids in the peptidoglycan are crucial for preserving bacterial cell structure and resistance to environmental threats. Herein, we characterized enzymatic and structural properties of TM0356 that shares a high amino acid sequence identity with serine (Ser) racemase. The results revealed that TM0356 forms a tetramer with each subunit containing a pyridoxal 5'-phosphate as a cofactor. The enzyme did not exhibit racemase activity toward various amino acids including Ser, and dehydratase activity was highest toward L-threonine (L-Thr). It also acted on L-Ser and L-allo-Thr, but not on the corresponding D-amino acids. The catalytic mechanism did not follow typical Michaelis-Menten kinetics; it displayed a sigmoidal dependence on substrate concentration, with highest catalytic efficiency (kcat/K0.5) toward L-Thr. Interestingly, dehydratase activity was insensitive to allosteric regulators L-valine and L-isoleucine (L-Ile) at low concentrations, while these L-amino acids are inhibitors at high concentrations. Thus, TM0356 is a biosynthetic Thr dehydratase responsible for the conversion of L-Thr to α-ketobutyrate and ammonia, which is presumably involved in the first step of the biosynthesis of L-Ile.

Case with metastatic cutaneous malignant melanoma that developed Vogt-Koyanagi-Harada-like uveitis following pembrolizumab treatment.

PURPOSE: The study reports a case with metastatic cutaneous malignant melanoma that developed Vogt-Koyanagi-Harada-like uveitis during pembrolizumab treatment. The uveitis improved by discontinuation of pembrolizumab and use of oral and topical steroids. Full-field flicker ERGs were used to monitor the retinal function before and after the steroid treatments. CASE REPORT: A 68-year-old women presented with blurred vision in both eyes 3 months after beginning pembrolizumab adjuvant therapy for a malignant melanoma on the lower thigh. Optical coherence tomography showed a serous retinal detachment (SRD) in the right eye and marked choroidal thickening in both eyes. Fluorescein angiography showed spotted hyperfluorescence in the right eye and leakage of fluorescein from both optic disks. Indocyanine green angiography showed dark hypofluorescent spots in both eyes. She was diagnosed with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab and discontinued the pembrolizumab. She was then treated with oral prednisolone and topical betamethasone. One week later, the symptoms were improved, and 1 month later the choroidal thickening in both eyes and the SRD of the right eye were not present. The implicit time of the full-field flicker ERGs recorded by RETeval system was significantly delayed at the initial examination but improved within a few weeks after the steroid replacement treatment. CONCLUSION: Our case with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab had a reduction in the degree of uveitis after discontinuation of the pembrolizumab and use of oral prednisolone and topical betamethasone. Flicker ERGs were helpful in monitoring the retinal function before and after the steroid treatment.

Case of cystoid macular edema induced by systemic administration of paclitaxel: evaluations with electroretinograms.

PURPOSE: To report abnormal full-field electroretinograms (ERGs) in a patient with cystoid macular edema (CME) induced by systemic paclitaxel. METHODS: This is an observational case report. Full-field ERGs were recorded to evaluate the retinal function using the RETeval system and conventional ERGs using contact lens electrodes with built-in white light-emitting diodes. Optical coherence tomography (OCT) was also used to assess the retinal morphology. RESULTS: A 70-year-old man, who was diagnosed with gastric cancer, had undergone gastrectomy. Subsequently, systemic paclitaxel was administered once a week as an adjuvant therapy. After the tenth course of paclitaxel, he experienced blurred vision in both eyes and visited our department of ophthalmology. OCT revealed the presence of CME in both eyes, and the RETeval flicker ERGs showed a marked reduction in the amplitudes and a prolongation of the implicit times in both eyes. Conventional ERGs showed that the amplitudes of the oscillatory potentials (OPs) were also severely attenuated. The abnormal OCT findings and reduced visual acuity recovered to normal at 1 and 2 months, respectively, after the discontinuation of paclitaxel. However, the flicker ERGs did not recover to normal values until 4 months after the discontinuation of paclitaxel. CONCLUSION: These results suggest that the ERGs can be used to monitor the changes in the overall retinal function in patients receiving paclitaxel.

Case of lens-induced uveitis associated with supernormal flicker ERG amplitudes after cataract surgery.

PURPOSE: To report our findings in a case of lens fragment-induced uveitis associated with supernormal flicker electroretinograms (ERGs) twenty months after the cataract surgery. METHODS: This is an observational case report. Full-field flicker ERGs were recorded with the RETeval system. Optical coherence tomography (OCT) and slit-lamp biomicroscopy were used to assess the uveitis during the follow-up period. RESULTS: A 70-year-old man, who had undergone cataract surgery 20 months earlier, visited our hospital with a complaint of decreased vision in his right eye. Slit-lamp biomicroscopy revealed corneal edema and a lens fragment was detected in the inferior part of the anterior chamber. OCT showed cystoid macular edema, and flicker ERGs showed a marked increase in the amplitude and a delay in the implicit time in the right eye. These abnormalities of the flicker ERGs improved gradually after the removal of lens fragment and application of topical anti-inflammatory medications. CONCLUSION: Our case of lens-induced uveitis had supernormal flicker ERG amplitudes. Clinicians should be aware that eyes with uveitis can have larger-than-normal ERG amplitudes.

A new method of adjusting mesh tension using cystoscopy during laparoscopic sacrocolpopexy.

We aimed to examine the usefulness of cystoscopic findings to guide mesh tension adjustment during laparoscopic sacrocolpopexy (LSC) to promote better repair of pelvic organ prolapse (POP) and prevent de novo stress urinary incontinence (SUI). In this technique, the bladder wall was observed using a cystoscope when various traction pressures were applied by pulling the mesh arm with forceps before fixation to the promontory during LSC. Adjustment was performed on 20 patients, and postoperative outcomes of POP repair and development of de novo SUI were evaluated. When excessive traction was applied on the mesh arm, a bladder neck opening and a cord-like elevation in the center of the trigone and posterior wall were observed in all cases. The tension was gradually loosened, and precisely when the above-mentioned cystoscopic finding ("Central Road") disappeared, an anatomically appropriate elevation of the vaginal apex was achieved; the mesh arm was fixed to the promontory. At 6 months after LSC, anterior wall recurrences were diagnosed in four patients (beyond the hymen in one) with few symptoms, while no occurrence of de novo SUI. Cystoscopic findings during mesh tension adjustment in LSC could be useful in achieving improved POP repair.

Hyperammonemic encephalopathy associated with post-radiotherapy vesicointestinal fistula following cervical cancer.

The majority of hyperammonemic encephalopathy is due to liver cirrhosis. However, urinary tract infection caused by urease-producing bacteria increases ammonia in urine and can lead to hyperammonemic encephalopathy, especially in cases with obstructive uropathy and vesicointestinal fistula. This is the first case report of hyperammonemic encephalopathy in a cervical cancer patient associated with postradiotherapy vesicointestinal fistula. A 52-year-old woman developed diarrhea due to vesicosigmoidal fistula 14 years after radical hysterectomy and radiotherapy to treat cervical cancer. She refused urinary and/or fecal diversion. Twelve months after the diagnosis of fistula, she was admitted due to somnolence. Blood examination showed hyperammonemia without liver dysfunction. Urine culture showed Proteus rettgeri and Klebsiella pneumoniae. She recovered after intravenous antibiotics. Eight months after recovery, she was readmitted due to somnolence reoccurring with failed intravenous, but successful oral antibiotic treatment. She finally agreed to undergo percutaneous nephrostomy and hyperammonemia never recurred during 7 years of follow-up.

Efficacy and safety of the noradrenaline reuptake inhibitor, TAS-303, in women with stress urinary incontinence: Results of a double-blind, randomized, placebo-controlled, early phase II trial.

OBJECTIVE: To carry out an exploratory assessment of the efficacy and safety of TAS-303, a noradrenaline reuptake inhibitor, in women with stress urinary incontinence. METHODS: In a double-blind, placebo-controlled, early phase II study, women with stress urinary incontinence and stress urinary incontinence-predominant mixed urinary incontinence were randomized to a placebo or TAS-303 (3 or 6 mg) once daily for 8 weeks. The main efficacy end-points were mean percentage change in incontinence episode frequency per 24 h from baseline to week 8 (the primary end-point) and week 4. RESULTS: At week 8, the mean percentage change in incontinence episode frequency per 24 h was -34.73% in the TAS-303 3 mg group, -35.41% in the TAS-303 6 mg group and -28.07% in the placebo group (differences vs placebo, not significant). In patients with stress urinary incontinence, or incontinence episode frequency less than two episodes per 24 h at baseline, TAS-303 significantly reduced incontinence episode frequency versus placebo after 4 weeks; some secondary end-points also showed a tendency to improve in the same subgroups. No serious adverse events (e.g. central nervous system or cardiovascular effects) were observed; TAS-303 was well tolerated and had a favorable safety profile. CONCLUSION: These findings suggest that TAS-303 is effective for improving stress urinary incontinence symptoms in some subgroups of patients with stress urinary incontinence. Therefore, further research is warranted.

Mesh exposure after transvaginal mesh prolapse surgery: Out of permissible range?

OBJECTIVES: To investigate the prevalence of postoperative complications after transvaginal mesh prolapse surgery, and whether modified transvaginal mesh prolapse surgery (without transobturator arms or posterior mesh) has less prevalence of mesh exposure compared with conventional transvaginal mesh prolapse surgery. METHODS: Medical charts were retrospectively examined for 2648 patients who underwent transvaginal mesh prolapse surgery in a general hospital (2006-2017). Conventional transvaginal mesh prolapse surgery (Prolift-type, n = 2258) was used, with a shift from 2015 to modified transvaginal mesh prolapse surgery (Uphold-type, n = 330). Patients were instructed to have >2 years of follow up and to report if they had problems regarding the operation. RESULTS: The prevalence of mesh exposure was 34 out of 2648 (1.28%); 18 vagina (0.68%), 10 bladder (0.38%), two ureter (0.08%) and four rectum (0.15%). The modified transvaginal mesh prolapse surgery group had only one case with vaginal exposure. Vaginal exposure was managed transvaginally or followed by observation. Rectal exposure was managed transvaginally without colostomy. Bladder exposure was managed by transurethral resection with saline. Open ureterocystostomy was carried out to treat ureteral exposure. In the conventional transvaginal mesh prolapse surgery group, three cases of ureteral stenosis and one case with vaginal evisceration of the small intestine were managed transvaginally. The prevalence of postoperative chronic pain was 13 out of 2648 (0.49%; with one patient in the modified transvaginal mesh prolapse surgery group). The patients underwent pharmacotherapy, and one patient underwent additional surgical treatment. CONCLUSIONS: The reoperation rate as a result of complications after transvaginal mesh prolapse surgery seems to be low. The reoperation rate as a result of prolapse recurrence is also low. A shift from conventional transvaginal mesh prolapse surgery to modified transvaginal mesh prolapse surgery might contribute to a further decrease in the risk of complications.