Predicting postpartum hemorrhage in women undergoing planned cesarean section: A multicenter retrospective cohort study in Japan.

Given Japan's unique social background, it is critical to understand the current risk factors for postpartum hemorrhage (PPH) to effectively manage the condition, especially among specific groups. Therefore, this study aimed to identify the current risk factors for PPH during planned cesarean section (CS) in Japan. This multicenter retrospective cohort study was conducted in two tertiary maternal-fetal medicine units in Fukushima, Japan and included 1,069 women who underwent planned CS between January 1, 2013, and December 31, 2022. Risk factors for PPH (of > 1000 g and > 1500 g) were assessed using multivariate logistic regression analysis, considering variables such as maternal age, parity, assisted reproductive technology (ART) pregnancy, pre-pregnancy body mass index (BMI), uterine myoma, placenta previa, gestational age at delivery, birth weight categories, and hypertensive disorders of pregnancy (HDP). Multivariate linear regression analyses were conducted to predict estimated blood loss during planned CS. ART pregnancy, a pre-pregnancy BMI of 25.0-29.9 kg/m2, and uterine myoma increased PPH risk at various levels. Maternal smoking increased the risk of >1500 g PPH (adjusted odds ratio: 3.09, 95% confidence interval [CI]: 1.16-8.20). Multivariate linear analysis showed that advanced maternal age (B: 83 g; 95% CI: 27-139 g), ART pregnancy (B: 239 g; 95% CI: 121-357 g), pre-pregnancy BMI of 25.0-29.9 kg/m2 (B: 74 g; 95% CI: 22-167 g), uterine myoma (B: 151 g; 95% CI: 47-256 g), smoking (B: 107 g; 95% CI: 13-200 g), and birth weight > 3,500 g (B: 203 g; 95% CI: 67-338 g) were associated with blood loss during planned CS. Considering a patient's clinical characteristic may help predict bleeding in planned CSs and help improve patient safety.

Hydropic leiomyoma-like ovarian tumor: a case report.

Uterine leiomyomas, benign tumors common in reproductive-aged women, can display rare variants such as hydropic leiomyoma (HL), which exhibit unique histological features like zonal edema and increased vascularity. However, due to its rarity, comprehensive clinical knowledge about HL is limited. We report a case of a 49-year-old Japanese woman who was premenopausal and nulliparous, presenting with a two-year history of abdominal distension. An MRI scan revealed a 20 cm mass in the posterior part of the uterus, exhibiting characteristics suggestive of an ovarian tumor. During laparotomy, a cystic tumor connected with a swollen fibroid was found, and pathology confirmed HL. This case emphasizes that hydropic leiomyomas can mimic malignant tumors on ultrasonography due to their atypical features, necessitating additional evaluations using alternative imaging techniques or histopathological examinations for accurate diagnosis and appropriate management. The patient recovered uneventfully, broadening our understanding of HL's clinical presentation.

Utility and optimal management of planned drug holidays during lenvatinib treatment in patients with unresectable differentiated thyroid cancer: a real-world multi-center study.

PURPOSE: Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions. METHODS: Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH. RESULTS: The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule. CONCLUSION: Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis.

Evaluation and treatment of constipation in pregnancy:Examination using the Japanese version of the constipation evaluation scale.

OBJECTIVES: No study has examined the effects of new constipation treatment drugs released in recent years in pregnant women. This prospective cohort study aimed to examine and compare the perinatal prognosis, efficacy rate, and safety of drugs frequently used to treat constipation. METHODS: The study included 211 perinatally managed individuals who answered a self-administered questionnaire during the second trimester and after delivery. The Japanese version of the constipation evaluation scale (Constipation Assessment Scale [CAS] long-term [LT] version) was used for the subjective evaluation of defecation status. RESULTS: Participants aware of constipation had significantly higher CAS scores than those who were unaware. Some participants with a CAS score of 5 points (treatment range) had no subjective symptoms of constipation, whereas some participants with a CAS score of ≤ 5 points were aware of constipation. Regarding the time of onset, 60% of those who had constipation before pregnancy had a high rate of constipation during pregnancy and after delivery. No significant difference was noted in conventional magnesium oxide and polyethylene glycol, a relatively new daily treatment drug, in perinatal prognosis or side effects. CONCLUSIONS: Polyethylene glycol preparations alleviate constipation without inducing diarrhea, making them an appropriate therapeutic option for pregnant women.

Association between Gestational Weight Gain and Risk of Hypertensive Disorders of Pregnancy among Women with Obesity: A Multicenter Retrospective Cohort Study in Japan.

The relationship between weight gain during pregnancy and the onset of hypertensive disorders of pregnancy in women with pre-pregnancy obesity remains unclear. We examined the effects of weight gain during pregnancy on hypertensive disorders of pregnancy among women with pre-pregnancy body mass index (BMI) ≥ 25.0 kg/m2. This multicenter retrospective cohort study included nullipara women who delivered at two units in Japan between 1 January 2013, and 31 December 2020. Singleton primipara (n = 3040) were categorized into two pre-pregnancy BMI groups: 25.0-<30.0, and ≥30.0 kg/m2. Using multiple logistic regression analyses (reported as adjusted odds ratio and 95% confidence interval), gestational weight gain effects on overall hypertensive disorders of pregnancy, gestational hypertension, and pre-eclampsia were determined. Gestational weight gain increased hypertensive disorders of pregnancy (1.09, 1.03-1.16, p < 0.05) and pre-eclampsia risk (1.10, 1.01-1.20, p < 0.05) among the BMI 25.0-<30.0 kg/m2 group and hypertensive disorders of pregnancy risk among the ≥30.0 kg/m2 group (1.07, 1.00-1.05, p < 0.05). Using receiver operating characteristic curve analyses, among the BMI 25.0-<30.0 kg/m2 group, for hypertensive disorders of pregnancy (area under the curve [AUC], 0.63, p < 0.05) and pre-eclampsia (AUC, 0.62; p < 0.05), the weight gain cut-off was 10.5 and 10.6 kg, with sensitivity/specificity of 0.47/0.73 and 0.50/0.73, respectively. For the BMI ≥30.0 kg/m2 group (AUC, 0.63, p < 0.05), the cut-off was 3.5 kg (sensitivity/specificity, 0.75/0.49). The optimal gestational weight gain for reducing hypertensive disorders of pregnancy among women with a pre-pregnancy BMI > 25 kg/m2 may facilitate personalized pre-conception counseling among women with obesity.

Molecular basis of carotid body tumor and associated clinical features in Japan identified by genomic, immunohistochemical, and clinical analyses.

Carotid body tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs.

Optimal gestational weight gain to reduce the risk of hypertension disorders of pregnancy among women with obesity: A single tertiary referral center study in Japan.

AIM: To examine the effect of weight gain during pregnancy on hypertension disorders of pregnancy among women with a prepregnancy body mass index ≥30.0 kg/m2 . METHODS: This retrospective cohort study included 257 Japanese women (116 primipara; 141 multipara) with singleton pregnancies with a prepregnancy body mass index ≥ 30.0 kg/m2 , who gave birth during 2013 to 2020 at Ohta Nishinouchi Hospital. Multiple logistic regression analyses were performed to identify the effect of gestational weight gain on early-onset (<34 weeks), late-onset (≥34 weeks), and overall hypertension disorders of pregnancy. RESULTS: The prevalence of hypertension disorders of pregnancy in primiparas and multiparas was 28.4% and 11.3%, respectively. By multiple logistic regression analysis, gestational weight gain during pregnancy increased the risk of early-onset (adjusted odds ratio: 1.20, 95% confidence interval: 1.03-1.39, p < 0.05) and overall hypertension disorders of pregnancy (adjusted odds ratio: 1.12, 95% confidence interval: 1.03-1.22, p < 0.05) among primiparas. Based on receiver operating characteristic curve analyses for early-onset (area under the curve 0.67, 95% confidence interval: 0.56-0.78; p < 0.05) and overall hypertension disorders of pregnancy (area under the curve 0.76, 95% confidence interval: 0.61-0.91; p < 0.05) among primiparas, we determined the cut-off weight gain during pregnancy for early-onset and overall hypertension disorders of pregnancy as 3.85 kg, with sensitivity/specificity of 0.76/0.59 and 0.91/0.53, respectively. CONCLUSION: We recommend that the optimal gestational weight gain for reducing HDP be under 3.85 kg. This information may facilitate personalized pre-conception counseling among women with obesity.

Comparative analysis of temperature preference behavior and effects of temperature on daily behavior in 11 Drosophila species.

Temperature is one of the most critical environmental factors that influence various biological processes. Species distributed in different temperature regions are considered to have different optimal temperatures for daily life activities. However, how organisms have acquired various features to cope with particular temperature environments remains to be elucidated. In this study, we have systematically analyzed the temperature preference behavior and effects of temperatures on daily locomotor activity and sleep using 11 Drosophila species. We also investigated the function of antennae in the temperature preference behavior of these species. We found that, (1) an optimal temperature for daily locomotor activity and sleep of each species approximately matches with temperatures it frequently encounters in its habitat, (2) effects of temperature on locomotor activity and sleep are diverse among species, but each species maintains its daily activity and sleep pattern even at different temperatures, and (3) each species has a unique temperature preference behavior, and the contribution of antennae to this behavior is diverse among species. These results suggest that Drosophila species inhabiting different climatic environments have acquired species-specific temperature response systems according to their life strategies. This study provides fundamental information for understanding the mechanisms underlying their temperature adaptation and lifestyle diversification.

A case of spontaneous parasitic myoma in a patient without a history of myomectomy treated laparoscopically.

Parasitic myoma (PM) is a rare disease in which multiple leiomyomas are intraperitoneally formed. Recently, an increasing number of cases due to specimen morcellation during minimally invasive surgery has been reported. We present the first case of a PM identified intraoperatively during laparoscopic hysterectomy. A 40-year-old Japanese multiparous woman presented to our hospital with heavy menstrual bleeding. She had no history of previous surgery. Magnetic resonance imaging showed uterine myomas. As the patient did not wish for further pregnancy, she underwent oral gonadotropin-releasing hormone antagonist therapy followed by a total laparoscopic hysterectomy. Intraoperatively, we identified a thumb-sized tumor on the left side of the peritoneum. Histopathological examination showed evidence of benign leiomyoma.

Introduction and utility of resuscitative endovascular balloon occlusion of the aorta for cases with a potential high risk of postpartum hemorrhage: A single tertiary care center experience of two cases.

Postpartum hemorrhage is an important obstetric complication and the leading cause of maternal mortality worldwide. Occasionally, we encounter unexpected massive postpartum hemorrhage diagnosed for the first time after delivery. Therefore, it is essential to pay attention to patients with a high risk of postpartum hemorrhage. The authors report two cases of patients at high risk of postpartum hemorrhage that were successfully managed by resuscitative endovascular balloon occlusion of the aorta before cesarean section. Case 1: A 32-year-old woman with a history of cesarean section and who conceived using assisted reproductive technology was diagnosed with partial placenta previa at 25 weeks of gestation. Because of tocolysis failure, emergent cesarean section with resuscitative endovascular balloon occlusion of the aorta was performed at 36 weeks of gestation. Natural placental resorption was observed. She was discharged at 5 days after delivery without significant hemorrhage. Case 2: A 41-year-old woman with suspected placenta accreta spectrum due to a cesarean scar pregnancy was referred to our hospital at 33 weeks of gestation. A planned cesarean section with resuscitative endovascular balloon occlusion of the aorta was conducted at 37 weeks of gestation. There was no visual evidence of abnormal placental invasion of the myometrium, and natural placental resorption was observed. She was discharged at 5 days after delivery without significant hemorrhage.

Risk factors for discontinuation of exclusive breast feeding within 1month: a retrospective cohort study in Japan.

BACKGROUND: While breastfeeding provides benefits for infants and the mother, many women either do not breastfeed or terminate breastfeeding earlier than recommended. The aim of this analysis was to identify factors associated with early discontinuation of breastfeeding in Japanese women. METHODS: This study used data from medical records of women delivering a singleton live birth between March 2017 and August 2019 in Iwase General Hospital, Fukushima Prefecture, Japan to assess cessation of breastfeeding by the 1-month postpartum appointment. Demographic (age at birth, and employment status), medical (parity, and physical and mental condition of the mother; and infant medical factors, such as sex, Apgar score, and jaundice, among other), and family factors (husband/partner, family members living at the same house, among others) in 734 women who had initiated breastfeeding during their delivery hospital stay were examined, and multiple logistic regression was used to determine significant predictors of early cessation of exclusive breastfeeding. RESULTS: Bivariate analysis revealed that women who were primipara, unmarried, exposed to secondhand smoke, and employed; those who smoked before pregnancy; and those who had asthma were more likely to discontinue exclusive breastfeeding than other women. Infant factors associated with discontinuation were lower birthweight, earlier gestational age, neonatal intensive care unit admission, treatment for jaundice, or lower weight gain. Multivariable analysis revealed that primiparity, passive smoking before pregnancy, maternal employment, and neonatal jaundice therapy were associated with discontinuation of breastfeeding. CONCLUSIONS: In particular, women whose partners smoked before pregnancy may need to be targeted for additional support for breastfeeding.

Tubo-ovarian abscess in a patient with cri du chat syndrome: A case report.

A tubo-ovarian abscess is an infection that occurs as a sequela of pelvic inflammatory disease. There is no reported association between a tubo-ovarian abscess and cri du chat syndrome in the medical literature. Herein, we report the case of a 44-year-old woman with cri du chat syndrome who was subsequently diagnosed with a tubo-ovarian abscess. After emergent laparotomy, simple total hysterectomy, and bilateral adnexectomy, the patient was discharged 13 days postoperatively without complications.

Carotid body tumor with neck metastasis due to germline SDHB variant: a case report and literature review.

Carotid body tumor involving the succinate dehydrogenase subunit B (SDHB) variant reportedly had a higher frequency of metastasis than other variants of succinate dehydrogenase. However, the correlation between genotype and phenotype among patients with carotid body tumor with SDHB gene variant remains unclear. Thus, we present a case of carotid body tumor with neck lymph metastasis caused by a novel SDHB variant, which resulted in long-term disease-free survival achieved after surgery. A 43-year-old man presented to our hospital with a 2-year history of a painless neck mass. Based on the radiographic findings, the patient was diagnosed with carotid body tumor with a possible Shamblin type III tumor. Another mass was detected and suspected to be a lymph node metastasis. The patient underwent resection of the tumor and lymph nodes. The common carotid artery, internal carotid artery, external carotid artery, internal jugular vein, vagal nerve, and hypoglossal nerve were resected with the tumor. Histopathological examination revealed a paraganglioma. The histological findings of the lymph nodes were similar to those of the carotid body tumor and were confirmed to be metastases of paraganglioma. To analyze the germline SDHx variant, a nonsense variant was detected in the SDHB gene at exon 2, c. 136C > T, p. Arg46*. During the follow-up 80 months after surgery, the patient exhibited no signs of recurrence, metastasis, or development of paragangliomas in other organs. This was the first case of carotid body tumor accompanied by neck metastasis caused by a germline nonsense SDHB variant at exon 2, c. 136C > T, p. Arg46*. Carotid body tumor with neck lymph metastasis caused by this nonsense variant could achieve long-term disease-free survival after surgery. Gene analysis, including SDHB variant, should be performed to predict the prognosis and future risk of metastasis. Genetic testing of SDHB may give a crucial information for the treatment and follow-up strategies of carotid body tumor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-021-00522-x.

Pregnancy complicated by central diabetes insipidus and oligohydramnios.

This is the fourth reported case of central diabetes insipidus with oligohydramnios. Central diabetes insipidus does not adversely affect pregnancy; it can present with oligohydramnios, which can be improved by treating central diabetes insipidus.

Cyclooxygenase-2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma.

Cyclooxygenase-2 (COX-2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is associated with the progression in various types of cancer, and its expression has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX-2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX-2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX-2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resection with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX-2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX-2 expression with stemness property, the expression levels of CSC-associated genes after exposure to celecoxib were assessed by reverse transcription-quantitative PCR. A sphere formation assay was also performed using ultra-low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX-2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX-2 inhibition led to downregulation of CSC-associated gene expression and sphere formation. The present findings suggested that COX-2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX-2 may enhance chemo-sensitivity in HNSCC. Therefore, COX-2 may be an attractive target for the treatment of HNSCC.

Selective EP2 and Cox-2 inhibition suppresses cell migration by reversing epithelial-to-mesenchymal transition and Cox-2 overexpression and E-cadherin downregulation are implicated in neck metastasis of hypopharyngeal cancer.

Cyclooxygenase-2 (Cox-2) has been shown to promote cancer initiation and progression through pleiotropic functions including induction of epithelial-to-mesenchymal transition (EMT) via its predominant product prostaglandin E2 that binds to the cognate receptor EP2. Hence, pharmacological inhibition at the level of EP2 is assumed to be a more selective alternative with less risk to Cox-2 inhibition. However, little is known regarding the anti-cancer effect of an EP2 antagonist on the malignant properties of cancers including hypopharyngeal squamous cell carcinoma (HPSCC). The present study found that both the Cox-2 inhibitor celecoxib and the EP2 antagonist PF-04418948 upregulated CDH-1 expression, restored membranous localization of E-cadherin, and reduced vimentin expression, by downregulating the transcriptional repressors of E-cadherin in BICR6 and FaDu cells. Such Cox-2 or EP2 inhibition-induced EMT reversal led to repressed migration ability in both cells. Immunohistochemical analysis of surgical HPSCC specimens demonstrated an inverse relationship in expression between Cox-2 and E-cadherin both in the context of statistics (P = 0.028) and of reciprocal immunolocalization in situ. Multivariate logistic regression revealed that overexpression of Cox-2 (P < 0.001) and downregulation of E-cadherin (P = 0.016) were both independently predictive of neck metastasis. These results suggest that suppression of cell migration ability via reversing EMT by inhibiting the Cox-2/EP2 signaling may contribute to preventing the development and progression of lymphatic metastasis. Collectively, targeting Cox-2/EP2, especially using EP2 antagonist, can be a promising therapeutic strategy by exerting an anti-metastatic effect via EMT reversal for improving the treatment outcomes of patients with various cancers including HPSCC.

Cyclo-oxygenase-2 Expression Is Associated With Lymph Node Metastasis in Oropharyngeal Squamous Cell Carcinoma Under the New TNM Classification.

BACKGROUND: This study aimed to investigate p16 and COX2 expression in oropharyngeal squamous cell carcinoma (OPSCC), and evaluate the prognostic role of COX2 expression under the new TNM classification. MATERIALS AND METHODS: Biopsy specimens obtained from 75 patients with OPSCC were stained for p16 and COX2 expression immunohistochemically. The results and clinical records were analyzed retrospectively. RESULTS: Fifty-nine patients (79%) were positive for p16. COX2 expression was correlated with poor relapse-free survival in patients overall, and in p16-positive patients. Smoking was positively associated with COX2 expression. Moreover, both positive COX2 expression and anterior wall tumor subsite were independently correlated with lymph node metastasis, which was the only independent prognostic factor in p16-positive OPSCC. CONCLUSION: The p16-positive rate in this study was comparable with that in the USA and Europe, and higher than that in other Asian countries. COX2 expression might affect the prognosis of p16-positive OPSCC through promoting lymph node metastasis.

Usefulness of Hematological Inflammatory Markers in Predicting Severe Side-effects from Induction Chemotherapy in Head and Neck Cancer Patients.

BACKGROUND: Induction chemotherapy (IC) for head and neck cancer (HNC) often causes severe side-effects. However, it has still been challenging to predict the adverse events. The present study aimed to evaluate the role of hematological inflammatory markers in predicting severe side-effects caused by IC. MATERIALS AND METHODS: A total of 54 HNC patients who underwent IC were enrolled. The association between severe side-effects and pre-treatment hematological inflammatory markers [the C-reactive protein (CRP) to albumin ratio (CAR), the modified Glasgow Prognostic Score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR)] were evaluated. RESULTS: In the univariate analysis, the incidence of whole severe side-effects (grade 4), febrile neutropenia (above grade 3), and hyponatremia (above grade 3) were significantly higher in the high CAR and high GPS groups. Multivariate analysis revealed that high CAR and mGPS were independent predictors of these side-effects. CONCLUSION: CAR and mGPS were significant predictors of severe side-effects. These data can potentially offer patients an improved quality of life during cancer therapy.

Frequent nonrandom shifts in the temporal sequence of developmental landmark events during teleost evolutionary diversification.

Morphological transformations can be generated by evolutionary changes in the sequence of developmental events. In this study, we examined the evolutionary dynamics of the developmental sequence on a macroevolutionary scale in teleosts. Using the information from previous reports describing the development of 31 species, we extracted the developmental sequences of 19 landmark events involving the formation of phylogenetically conserved body parts; we then inferred ancestral developmental sequences by two different parsimony-based methods-event-pairing and continuous analysis. The phylogenetic comparisons of these sequences revealed event-dependent heterogeneity in the frequency of sequence changes. Most of the sequence changes occurred as exchanges of temporally neighboring events. These heterochronic changes in developmental sequences accumulated along evolutionary time, but the precise distribution of the changes over the teleostean phylogeny remains unclear due to technical limitations.