Fertility preservation after gonadotoxic treatments for cancer and autoimmune diseases.

BACKGROUND: The indications for fertility preservation (FP) have expanded. A few patients who underwent gonadotoxic treatment did not have the opportunity to receive FP, leading to concerns that these patients may develop premature ovarian insufficiency. However, the usefulness of FP in women with reduced ovarian reserve has also been questioned. Progestin-primed ovarian stimulation can improve the controlled ovarian stimulation (COS) protocol, but there is limited data on the efficacy of FP with progestin-primed ovarian stimulation. METHODS: We conducted a prospective study of 43 women with cancer or autoimmune diseases before and after gonadotoxic treatment at the reproductive unit of Keio University Hospital, counselled between 1 January 2018 and 31 December 2021. After counselling, informed consent was obtained for FP from 43 patients, with those who underwent gonadotoxic treatment of the primary disease being prioritised. Gonadotropin-releasing hormone analogue or progestin was used to suppress luteinising hormone in COS before or after gonadotoxic treatment. The number of cryopreserved mature oocytes was the primary outcome. RESULTS: Forty-three patients and 67 assisted reproductive technology cycles were included in the analysis. The median age at entry was 32 [inter quartile range (IQR), 29-37] years. All patients in the post-gonadotoxic treatment group had their oocytes frozen. Gonadotoxic treatment resulted in fewer oocytes [median 3 (IQR 1-4); pre-gonadotoxic treatment group: five patients, 13 cycles] vs. median 9 (IQR 5-14; pre-gonadotoxic treatment group: 38 patients, 54 cycles; P < 0.001). Although anti-Müllerian hormone levels were lower in the post-gonadotoxic treatment group (n = 5, 13 cycles, median 0.29 (IQR 0.15-1.04) pg/mL) than in the pre-gonadotoxic treatment group (n = 38, 54 cycles, median 1.89 (IQR 1.15-4.08) pg/mL) (P = 0.004), oocyte maturation rates were higher in the post-gonadotoxic treatment group [median 100 (IQR 77.5-100) %] than in the pre-gonadotoxic group [median 90.3 (IQR 75.0-100) %; P = 0.039]. Five patients in the pre-gonadotoxic treatment group had their cryopreserved embryos thawed, of which three had live births. CONCLUSIONS: Oocytes obtained for FP from women with cancer or autoimmune disease for FP are of satisfactory quality, regardless of whether they are obtained post-gonadotoxic treatment or COS protocols.

Morphometric assessment of blastocysts: relationship with the ongoing pregnancy rate.

Objective: To explore a morphometric grading system for blastocysts that is associated with ongoing pregnancy. Design: Cross-sectional study. Setting: None. Patientss: All consecutive vitrified blastocysts at our center from July 2018 to November 2021 that were transferred in single blastocyst transfer cycles until January 2022. Interventions: None. Main Outcome Measures: The ongoing pregnancy rate after a single vitrified-warmed blastocyst transfer. Interobserver agreement on morphometric values among embryologists. Results: Three morphometric variables (blastocyst diameter, area of inner cell mass [ICM], and the estimated trophectoderm cell count) were used to evaluate the expansion, ICM, and trophectoderm morphology. During the study period, 585 blastocysts were involved in this study. Of the 3 morphometric variables, ICM area (per 500 µm2, adjusted odds ratio, 1.19; 95% confidence interval, 1.09-1.30) and estimated trophectoderm cell count (per 10 cells, adjusted odds ratio, 1.25; 95% confidence interval, 1.12-1.39) were significantly associated with the ongoing pregnancy rate after adjustment for confounding factors. The ongoing pregnancy rate was 2.0% (1/49) with an ICM area of <2,500 µm2 and the estimated trophectoderm cell count <70. The ongoing pregnancy rate reached 47.8% (22/46) when the ICM area and the estimated trophectoderm cell count were >3,500 µm2 and >110, respectively. Interobserver agreement on the blastocyst diameter, ICM area, and the estimated trophectoderm cell count was excellent-to-good among 5 embryologists (intraclass correlation coefficients: 0.99, 0.87, and 0.91, respectively). Conclusions: Morphometric values of ICM and trophectoderm are promising predictors of pregnancy success. The high reproducibility suggests that the morphometric variables will contribute to identifying blastocysts with the highest developmental potential as well as those that will not result in a successful pregnancy.

Prevention of acute graft-versus-host disease in adult T-cell leukemia-lymphoma patients who received mogamulizumab before allogeneic hematopoietic cell transplantation.

Mogamulizumab (Mog) is effective against adult T-cell leukemia-lymphoma (ATL), but as we reported previously, Mog increases the incidence of severe acute GVHD when administered before allogeneic hematopoietic cell transplantation (allo-HCT). Here, we report the cases of two ATL patients who did not develop acute GVHD despite receiving Mog before allo-HCT. Case 1: a 63-year-old female who underwent allo-HCT from an HLA-matched donor 2 months after the last dose of Mog. Case 2: a 47-year-old male with ATL that relapsed 3 months after first allo-HCT. He received eight doses of Mog and underwent a second allo-HCT from a haploidentical donor 4 months after the last dose of Mog. Mog blood levels were measured and lymphocytes analyzed by mass cytometry. Mog blood levels measured before starting the conditioning regimens were low. A small proportion of regulatory T cells (Tregs) was detected before and shortly after allo-HCT. When using Mog before allo-HCT, it is important to consider the number of Mog doses and the interval from the last dose of Mog to allo-HCT. Analyzing Mog blood levels and Treg counts before and after allo-HCT should also be useful.

Neuroprotective effects of aromatic turmerone on activity deprivation-induced apoptosis in cerebellar granule neurons.

Ar-turmerone, which is a major bioactive component found in the essential oil derived from Curcuma longa, has been reported to inhibit proliferation and induce apoptosis in cancer cell lines. Recently, ar-turmerone has been reported to increase the proliferation of neuronal stem cells, in contrast to its actions in cancer cells. These observations raise the possibility that ar-turmerone serves specific functions in neuronal cell lineages. However, the effects of ar-turmerone on postmitotic neurons remain elusive. In the present study, we investigated the neuroprotective functions of ar-turmerone in primary cerebellar granule neuronal cultures. We found that ar-turmerone increased the survival of neurons following activity deprivation. Consistently, the induction of cleaved caspase-3, a hallmark of apoptosis, was prevented by ar-turmerone, although neither the level of reactive oxygen species nor the mitochondrial membrane potential was affected. This study reports a neuroprotective function for ar-turmerone, providing new insights into the potential therapeutic applications of ar-turmerone for neurological disorders.

Outcome of primary vitrectomy in phakic patients aged younger than 50 years with rhegmatogenous retinal detachments.

PURPOSE: To evaluate the visual outcome, primary anatomic success, and cataract progression of phakic eyes of patients aged younger than 50 years treated for rhegmatogenous retinal detachment (RRD) with primary pars plana vitrectomy (PPV). METHODS: This was a retrospective, observational, cross-sectional study. The data from 53 RRD patients undergoing PPV were analyzed. The time course changes in best-corrected visual acuity (BCVA) and cataract formation were examined. RESULTS: The 53 patients had a mean age of 37.8 years. Forty-eight eyes (90.6 %) achieved anatomic success after the primary surgery. The BCVA improved significantly after surgery (mean ± SD -0.091 ± 0.146) when compared with the baseline (mean ± SD 0.214 ± 0.597; P = 0.0001). No patient aged younger than 40 years (mean 32.5 years; range 17-39) developed significant lens opacity or received cataract surgery within the first 3 years. Of the patients aged older than 40 years (mean 43.8 years; range 40-49), 22 % developed significant lens opacity and received cataract surgery within the first 3 years. A significant difference was found in cataract progression between the two groups within the first 3 years (P = 0.0217), but not over the entire follow-up period (P = 0.1679). CONCLUSIONS: We found that lens-sparing PPV for RRD in patients aged younger than 50 years had a reasonable success rate, although cataract progression was evident during the follow-up period in patients aged older than 40 years.

A comparison of patient pain and visual outcome using topical anesthesia versus regional anesthesia during cataract surgery.

PURPOSE: The purpose of this study was to compare the level of patient pain during the phacoemulsification and implantation of foldable intraocular lenses while under topical, intracameral, or sub-Tenon lidocaine. PATIENTS AND METHODS: This was a retrospective study. Three hundred and one eyes subjected to cataract surgery were included in this study. All eyes underwent phacoemulsification surgery and intraocular lens implantation using topical, sub-Tenon, or intracameral anesthesia. The topical group received 4% lidocaine drops, and the intracameral group received a 0.1-0.2 cc infusion of 1% preservative-free lidocaine into the anterior chamber through the side port combined with topical drops of lidocaine. The sub-Tenon group received 2% lidocaine. Best-corrected visual acuity, corneal endothelial cell loss, and intraoperative pain level were evaluated. Pain level was assessed on a visual analog scale (range 0-2). RESULTS: There were no significant differences in visual outcome and corneal endothelial cell loss between the three groups. The mean pain score in the sub-Tenon group was significantly lower than that in the topical and intracameral groups (P=0.0009 and P=0.0055, respectively). In 250 eyes without high myopia (< -6D), there were no significant differences in mean pain score between the sub-Tenon and intracameral groups (P=0.1417). No additional anesthesia was required in all groups. CONCLUSION: Intracameral lidocaine provides sufficient pain suppressive effects in eyes without high myopia, while sub-Tenon anesthesia is better for cataract surgery in eyes with high myopia.

Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis.

Aberrant expression of regulators for epigenetics is involved in tumorigenesis. There is an urgent need to identify and characterize regulators concerned with epigenetics in the early stages of hepatocarcinogenesis. In the present study, we found that the expression of coactivator-associated arginine methyltransferase 1 (CARM1), a histone methyltransferase that functions as a cofactor for nuclear hormone receptors and several transcription factors, was elevated in adenomas and aberrant in carcinomas during hepatocellular carcinogenesis. In addition to RNA expression, immunohistochemical staining of liver sections revealed that CARM1 was highly expressed in the nucleus of tumor marker glutathione S-transferase placental form (GST-P)-positive foci. Neoplastic transformation of GST-P-positive foci guides the formation of hepatocellular carcinomas. CARM1 expression was not elevated in GST-P-negative regions. Furthermore, a luciferase reporter analysis revealed that CARM1 activated the Gst-p promoter in H4IIE, a hepatocellular carcinoma cell line. This activation was mediated by the enhancer element responsible for the carcinogenic-specific expression of Gst-p and nuclear factor E2-related factor 2. Knockdown of Carm1 by shRNA in H4IIE cells inhibited cell proliferation. These findings suggest that aberrantly expressed CARM1 in tumor marker-positive cells promotes tumorigenesis in the early stages of hepatocarcinogenesis.

Efficacy of inverted internal limiting membrane flap technique for the treatment of macular hole in high myopia.

PURPOSE: To determine the effect of pars plana vitrectomy (PPV) with inverted internal limiting membrane (ILM) flap technique for macular hole with or without retinal detachment in highly myopic eyes. DESIGN: Retrospective, interventional case series. METHODS: Ten eyes of 10 patients with macular hole with (4 eyes) or without (6 eyes) retinal detachment in high myopia (axial length more than 26.5 mm) were treated by PPV with inverted ILM flap technique. RESULTS: Macular hole closure was observed in 8 eyes (80%) following the initial surgery (in 5 eyes without retinal detachment and in 3 eyes with retinal detachment). In 4 eyes with retinal detachment caused by macular hole, retinas of 3 eyes were reattached by the initial surgery. Postoperative best-corrected visual acuity improved by more than 2 lines in 5 eyes (50%), was unchanged in 4 eyes (40%), and worsened by more than 2 lines in 1 eye (10%). CONCLUSIONS: Inverted ILM flap technique might contribute to a high closure rate of macular hole and be a preferable adjuvant to the treatment of macular hole in high myopia with or without retinal detachment.

The apoptosis-inducing protein kinase DRAK2 is inhibited in a calcium-dependent manner by the calcium-binding protein CHP.

Calcineurin homologous protein (CHP) is an EF-hand Ca(2+)-binding protein capable of interacting with various cellular proteins including Na(+)/H(+) exchangers, kinesin-related proteins, and apoptosis-inducing protein kinase DRAK2. We investigated the role of CHP on the DRAK2 protein kinase in vitro. CHP significantly reduced (approximately 85% inhibition) the kinase activity of DRAK2 for both autophosphorylation and phosphorylation of exogenous substrate (myosin light chain). The inhibitory effect of CHP was dependent on the presence of Ca(2+), whereas the interaction between CHP and DRAK2 was not Ca(2+)-dependent. These observations suggest that CHP negatively regulates the apoptosis-inducing protein kinase DRAK2 in a manner that depends on intracellular Ca(2+)-concentration.

Inferior alveolar nerve paresthesia relieved by microscopic endodontic treatment.

We experienced two cases of inferior alveolar nerve paresthesia caused by root canal medicaments, which were successfully relieved by microscopic endodontic treatment. In the first case, the paresthesia might have been attributable to infiltration of calcium hydroxide into the mandibular canal through the root canals of the mandibular left second molar tooth. In the second case, the paresthesia might have been attributable to infiltration of paraformaldehyde through the root canals of the mandibular right second molar tooth. The paresthesia was relieved in both cases by repetitive microscopic endodontic irrigation using physiological saline solution in combination with oral vitamin B12 and adenosine triphosphate.

Response of the mouse lens to varying sizes of injured area.

PURPOSE: To examine the response of the lens to varying sizes of perforating injury. METHODS: Four-week-old mice were used. Injuries consisted of pricking in the central region of the lens by transcorneal insertion of needles of two different sizes. After injury, the eyeballs were removed sequentially at various intervals up to 30 days and examined morphologically. RESULTS: The mouse lens showed three patterns of reaction; retained transparency, posterior opacity, and anterior opacity. (1) When the lens remained clear, the injury was small in area. The damaged portion of the lens was repaired by epithelial proliferation. (2) When opacity occurred abruptly at the posterior cortical area, epithelial damage was mild and lens fiber damage was relatively severe. Evans blue dye moved toward the posterior polar region along the cortical fiber arrangement. (3) When opacity developed abruptly at the anterior cortex, the size of epithelial damage and the damage to lens fibers were extensive. The posterior cortex remained transparent. Evans blue dye remained in the anterior polar region just beneath the injured part. CONCLUSION: It was found that the size of the injured area is a determinant of repair or opacity, and the site of opacity is dependent on the severity of epithelial damage and the location of the liquefied area.

Morphological analysis of iodoacetic acid-induced cataract in the rat.

PURPOSE: To clarify the mechanism underlying the development of cataract in the rat lens after intraperitoneal administration of iodoacetic acid (IAA). METHODS: (1) The 2% IAA dissolved in saline solution was injected at a dose of 40 mg/kg body weight into the rat peritoneal cavity. The retina and lens were intermittently extirpated and were examined by light and electron microscopy. (2) Two kinds of tracer, Evans blue (EB) and horseradish peroxidase (HRP), were injected into the tail veins and anterior chamber, and were observed with dissecting and electron microscopes. RESULTS: (1) Four weeks after administration, a part of the lens epithelium at the lateral side of the lens was degenerated, and the lens nucleus developed faint turbidity after 8 weeks. After 16 weeks, the nuclear turbidity could not be observed because mild cortical opacity was developing. The epithelial degeneration recovered from around 12 weeks, and instead of spherical nuclei, elliptical nuclei appeared. (2) The EB dye injected into the tail vein significantly stained the ciliary body, where the anterior and posterior ciliary arteries anastomosed. EB injected from the lateral side of the lens was seen to move towards the lens nucleus. Electron microscopically, the epithelial degeneration of the ciliary body was observed. The incorporated HRP substance was found in the cytoplasm of the nonpigmented cells of the ciliary epithelium at an early stage after IAA administration. CONCLUSION: IAA injected intravenously first developed epithelial degeneration at the lateral side of the lens. This change induced swelling of the lens fibers in the lens nucleus. Recovered epithelial cells had a transformed nucleus, and in turn the cortical cataract was induced by a differentiation disorder of the lens fibers. These results indicate that the breakdown of the blood-aqueous barrier in the nonpigmented epithelium of the ciliary body is a trigger to cause the cataract. The IAA-induced cataract may be useful as an animal model of human age-related cataract.